WO2022194191A1 - Composés hétérocycliques utilisés en tant qu'inhibiteurs de kras g12d - Google Patents
Composés hétérocycliques utilisés en tant qu'inhibiteurs de kras g12d Download PDFInfo
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- WO2022194191A1 WO2022194191A1 PCT/CN2022/081086 CN2022081086W WO2022194191A1 WO 2022194191 A1 WO2022194191 A1 WO 2022194191A1 CN 2022081086 W CN2022081086 W CN 2022081086W WO 2022194191 A1 WO2022194191 A1 WO 2022194191A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkylene
- alkyl
- formula
- compound
- aryl
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title abstract description 15
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 150000003839 salts Chemical class 0.000 claims abstract description 65
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 13
- 201000011510 cancer Diseases 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims description 42
- 125000003118 aryl group Chemical group 0.000 claims description 31
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 125000004429 atom Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 2
- 206010009944 Colon cancer Diseases 0.000 claims description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 2
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 2
- 201000002528 pancreatic cancer Diseases 0.000 claims description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- 102200006539 rs121913529 Human genes 0.000 abstract description 18
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- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 74
- -1 cyclic hydrocarbon radical Chemical class 0.000 description 71
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- 239000011734 sodium Substances 0.000 description 39
- 125000004432 carbon atom Chemical group C* 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- 239000012044 organic layer Substances 0.000 description 34
- 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
- 239000004698 Polyethylene Substances 0.000 description 31
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 22
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 15
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 description 11
- 238000009472 formulation Methods 0.000 description 10
- 125000004404 heteroalkyl group Chemical group 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
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- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 8
- 125000002947 alkylene group Chemical group 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- QYSRSSAJUOKVNM-UHFFFAOYSA-N 2-[8-ethyl-3-(methoxymethoxy)naphthalen-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C(C)C=1C=CC=C2C=C(C=C(C=12)B1OC(C(O1)(C)C)(C)C)OCOC QYSRSSAJUOKVNM-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
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- 229940079593 drug Drugs 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
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- 229960001866 silicon dioxide Drugs 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- HNINFCBLGHCFOJ-UHFFFAOYSA-N tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1NCC2CCC1N2C(=O)OC(C)(C)C HNINFCBLGHCFOJ-UHFFFAOYSA-N 0.000 description 6
- 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 5
- AHPVHEAQLFAZOC-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol Chemical compound C1CCN2CCCC21CO AHPVHEAQLFAZOC-UHFFFAOYSA-N 0.000 description 5
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- 125000002950 monocyclic group Chemical group 0.000 description 5
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- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 4
- OUVMXTXPILKKLK-UHFFFAOYSA-N 2-[6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-1-yl]ethynyl-tri(propan-2-yl)silane Chemical compound COCOC1=CC(B2OC(C)(C)C(C)(C)O2)=C2C(C=CC=C2C#C[Si](C(C)C)(C(C)C)C(C)C)=C1 OUVMXTXPILKKLK-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
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- ILTXDPMYCUSDQV-UHFFFAOYSA-N 2,4,7-trichloro-8-fluoropyrido[4,3-d]pyrimidine Chemical compound C1(=C(C2=C(C=N1)C(Cl)=NC(=N2)Cl)F)Cl ILTXDPMYCUSDQV-UHFFFAOYSA-N 0.000 description 3
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 3
- UQERDTKJRJNCHD-UHFFFAOYSA-N 7-chloro-8-fluoro-1H-pyrido[4,3-d]pyrimidine-2,4-dione Chemical compound C1(=C(C2=C(C=N1)C(=O)NC(=O)N2)F)Cl UQERDTKJRJNCHD-UHFFFAOYSA-N 0.000 description 3
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- MENILFUADYEXNU-UHFFFAOYSA-N tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate Chemical compound C1C(=O)CC2CCC1N2C(=O)OC(C)(C)C MENILFUADYEXNU-UHFFFAOYSA-N 0.000 description 1
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- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to heterocyclic compounds as inhibitors of the KRAS G12D mutant, and compositions containing these compounds which may be used to treat various disease conditions associated with KRAS G12D, such as cancers.
- RAS proteins are small, membrane-bound guanine nucleotide-binding proteins; they act as molecular switches by cycling between active GTP-bound and inactive GDP-bound conformations.
- KRAS G12D mutation The most frequent site of oncogenic mutation in KRAS is residue G12, with G12D mutation (glycine-12 to aspartate) as one of the frequent mutations at this residue.
- KRAS G12D mutation is found in ⁇ 4%of non-small cell lung adenocarcinoma, 1.7%of all small cell lung carcinoma, ⁇ 25%of pancreatic and 13%colorectal adenocarcinomas, respectively.
- KRAS G12D mutation Given the role and the frequency of KRAS G12D mutation in human cancers, there is a strong need for new medical treatments for patients with cancers characterized by KRAS G12D mutation.
- the present invention describes inhibitors of KRAS G12D.
- the present invention further describes pharmaceutical formulations that include an inhibitor of KRAS G12D.
- the invention features a compound of Formula I, or a pharmaceutically acceptable salt thereof:
- X and X 1 are independently selected from a bond, O, S, S (O) 2 , CH 2 , CHF, CF 2 or NR x provided that at least one of X and X 1 is NR x ;
- X 2 is CH 2 or absent
- W is C, CH, C (C 1-6 alkyl) or N;
- R x is H, C 1-3 alkyl, cyclopropyl
- R 1 is H, NR a R b , C 1-3 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-3 alkoxy, NH-C 1-3 alkyl, N (C 1-3 alkyl) 2 , CO 2 R 8 , CONR a R b or a 5-6 membered heteroaryl;
- R 2 is halo, C 1-6 alkyl. C 1-6 haloalkyl, C 1-6 alkoxy, -Y-heterocyclyl, -Y-aryl, -Y-heteroaryl, -Y-cycloalkyl, -Y-NR a R b , -Y-C (O) NR a R b , -Y-haloalkyl, -Y-OR a , -Y-NR a C (O) aryl, -Y-CO 2 R a , or -Y-NR c C (O) NR a R b , -Y-S (O) 2 aryl, -Y-S (O) 2 C 1-6 alkyl, S (O) 2 NR a R b , wherein the part of R 2 maybe optionally substituted with 0-3 occurrences of R 10 whenever valence rule is permitted;
- Z is a bond, O, S, or NR c ;
- R 3 is an aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with 0-4 occurrences of R 10 ;
- R 4 , R 5 , R 6 and R 7 are independently selected from H, halogen, -CN, C 1 -C 3 alkyl, C 3 - 6 cycloalkyl, C 3 - 6 halocycloalkyl or C 1 -C 3 haloalkyl;
- R 8 and R 9 are independently selected from H, C 1 -C 3 alkyl, C 3 - 6 cycloalkyl;
- R a , R b and R c are independently hydrogen or C 1-6 alkyl, -C 0-6 alkylene-C 6-10 aryl, -C 0-6 alkylene-5-10 membered heteroaryl or 5-10 membered heterocycly (preferably, hydrogen or C 1-6 alkyl, C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl) ; or R a and R b are taken together with the atom (s) to which they are attached to form an optionally substituted 5-10 membered carbocyclyl, or heterocyclyl which is optionally substitute with 0-5 occurrences of R 10 ; R b , R c and R e are independently substituted with 0-5 occurrences of R 10 ;
- R 10 is independently selected from C 1-6 alkyl, C 1-6 alkoxy, halo, hydroxy, oxo, amino, N (C 1-6 alkyl) 2 , cyano, C 0- 6 alkylene-NR b R a , C 0-6 alkylene-NR b R a , C 0-6 alkylene-C (O) NR b R a , C 0-6 alkylene-NR a C (O) R b , C 0-6 alkylene-S (O) 2 R b , C 0- 6 alkylene-S (O) 2 NR a R b , C 0-6 alkylene-NR c S (O) 2 R b , C 0-6 alkylene-NR c S (O) 2 NR a R b , C 0-6 alkylene-P (O) R a R b , C 0-6 alkylene-P (O) (OR c ) (OR b )
- R 11 and R 12 are independently selected from H, F, C 1 -C 3 alkyl, C 3 - 6 cycloalkyl, C 1 -C 3 haloalkyl or cyclopropyl;
- Each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl can be substituted with the substituents which are defined in the section of Definitions.
- the compound of Formula I is shown as Formula II;
- the invention further provides a compound of Formula III or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula IV or a pharmaceutically acceptable salt thereof:
- R x , Z, R 1 , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula V or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula VI or a pharmaceutically acceptable salt thereof:
- R x , Z, R 1 , R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula VII or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula VIII or a pharmaceutically acceptable salt thereof:
- R x , Z, R 1 , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula IX or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula X or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XI or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XII or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XIII or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XIV or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XV or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XVI or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula XVII or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula XVIII or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula XIX or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula XX or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula XXI or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula XXII or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula XXIII or a pharmaceutically acceptable salt thereof:
- R 2 , R 3 and R 4 are defined as in Formula I.
- the compound of Formula I is shown as formula II-A;
- the invention further provides a compound of Formula III-A or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula IV-A or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula V-A or a pharmaceutically acceptable salt thereof:
- the compound of Formula I is shown as Formula II-B;
- V 1 is CR 9 or N; Y, R 1 , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula III-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula IV-B or a pharmaceutically acceptable salt thereof:
- V 1 is CH or N; R 2 , R 3 and R 4 are defined as in Formula I.
- the invention further provides a compound of Formula V-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula VI-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula VII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R c , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula VIII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula IX-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N;
- X is CH 2 , O or NR x ;
- R x , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula X-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N;
- X is CH 2 , O or NR x ;
- R x , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XI-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N;
- X is CH 2 , O or NR x ;
- R x , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R x , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XIII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R x , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XIV-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R c , R x , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XV-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XVI-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XVII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R c , R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XVIII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XIX-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XX-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I; Z is selected from:
- the invention further provides a compound of Formula XXI-B or a pharmaceutically acceptable salt thereof:
- the invention further provides a compound of Formula XXII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XXIII-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I.
- the invention further provides a compound of Formula XXIV-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I; Z is selected from:
- the invention further provides a compound of Formula XXV-B or a pharmaceutically acceptable salt thereof:
- V 1 is CR 9 or N; R 2 , R 3 , R 4 and R 9 are defined as in Formula I; Z is selected from:
- a compound of Formula I to Formula XXV-B is selected from a stereoisomer, an enantiomer, or an atropoisomeric or a pharmaceutically acceptable salt thereof.
- a compound of Formula I to Formula XXV-B is selected from the following compounds or a stereoisomer, an enantiomer, or an atropisomer of them, or a pharmaceutically acceptable salt thereof:
- the invention features a pharmaceutical composition
- a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound disclosed herein.
- the invention features a method for treating a disease mediated by KRAS G12D mutant.
- the method comprises administering a therapeutically effective amount of a compound disclosed herein to a subject.
- the invention features a method of treating any of the following conditions by administering a therapeutically effective amount of a compound disclosed herein to a subject: pancreatic cancer, colorectal cancer, hepatocellular carcinoma, breast cancer, ovarian cancer, lung cancer, liver cancer, a sarcoma, or any other forms of cancer.
- the invention includes all possible combinations of the embodiments described above and below.
- alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C 1 - 10 means one to ten carbons) .
- saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
- An unsaturated alkyl group is one having one or more double bonds or triple bonds.
- alkyl groups examples include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl) , 2, 4-pentadienyl, 3- (1, 4-pentadienyl) , ethynyl, 1-and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
- Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl” .
- the said alkyl is optionally substituted with one or more halogen atom (s) .
- halogenated alkyl or “haloalkyl” means alkyl as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
- an alkyl (or alkylene) group has from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
- a "lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
- the said alkylene is optionally substituted with one or more halogen atom (s) .
- alkenylene means carbon chains which contain at least one carbon-carbon double bond, which may have (E) -or (Z) -geometry.
- alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof.
- alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
- the said alkynyl is optionally substituted with one or more halogen atom (s) .
- cycloalkyl means mono-or bicyclic saturated carbocyclic rings, each of which has from 3 to 10 carbon atoms.
- a “fused analog” of cycloalkyl means a monocyclic ring fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
- the said cycloalkyl is optionally substituted with one or more halogen atom (s) .
- alkoxy means alkoxy groups of a straight or branched having the indicated number of carbon atoms.
- C 1- 6 alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
- heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
- the heteroatom (s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
- heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH 2 -CH 2 -S-CH 2 -CH 2 -and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
- heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like) .
- chain termini e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like.
- no orientation of the linking group is implied by the direction in which the formula of the linking group is written.
- heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C (O) R', -C (O) NR', -NR'R", -OR', -SR', and/or -SO 2 R'.
- heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
- cycloalkoxy means cycloalkyl as defined above bonded to an oxygen atom, such as cyclopropyloxy.
- halogenated alkoxy means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by halogen atoms.
- aryl means mono-, bicyclic or tricyclic aromatic rings containing only carbon atoms.
- a “fused analog” of aryl means an aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2, 3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1, 4-benzodioxanyl, and the like.
- heteroaryl means a mono-, bicyclic or tricyclic aromatic rings containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
- a “fused analog” of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
- heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo (2, 3-b) pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
- heterocyclyl means mono-, bicyclic, tricyclic, spirocyclic, fused or bridged saturated ring systems containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
- a “heterocyclyl” includes a “fused analog” which means a monocyclic heterocycle fused to an heterocycle, a carbocycle, an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
- heterocyclyl and fused analogs thereof include azeridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dioxolanyl, oxazolodinyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, thiomorphonulyl 1, 1-dioxide, morpholinyl, azapanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyl, azabycyclononanyl, azaspiroheptanyl, dihydro-1H, 3H, 5H-oxazolo [3, 4-c] oxazolyl, tetroxazolyl,
- the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2-or 4-pyridones attached through the nitrogen or N-substituted- (1H, 3H) -pyrimidine-2, 4-diones (N-substituted uracils) .
- alkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups and heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents.
- the said substituents are selected from the group consisting of halogen atoms, hydroxyl group, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups,
- halo or halogen, by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl, “ or “halogenated alkyl” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo (C 1 -C 4 ) alkyl” is mean to include, but not be limited to, trifluoromethyl, 2, 2, 2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
- prodrug refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
- An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the "prodrug” ) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility, but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
- a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
- Compounds of Formula I to Formula XXV-B may contain one or more asymmetric centers/hindered rotation about a single bond, and may thus occur as racemates and racemic mixtures, single enantiomers, single atropisomers, diastereomeric mixtures and individual diastereomers.
- the present invention is meant to comprehend all such isomeric forms of the compounds of Formula I to Formula XXV-B.
- Some of the compounds of Formula I to Formula XXV-B may contain one or more than one cyclic ring systems and may thus exist in cis-and trans-isomers.
- the present invention is meant to include all such cis-and trans-isomers.
- tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I to Formula XXV-B.
- Compounds of the Formula I to Formula XXV-B may be separated into diastereoisomeric pairs of enantiomers by, for example, HPLC or fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof.
- a suitable solvent for example MeOH or EtOAc or a mixture thereof.
- the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine or acid as a resolving agent or on a chiral HPLC column.
- any enantiomer of a compound of the general Formula I to Formula XXV-B may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
- One or more than one of the protons in compounds of Formula I to Formula XXV-B can be replaced with deuterium atom (s) , thus providing deuterated analogs that may have improved pharmacological activities.
- the compounds described herein can be useful as the free base or as a salt.
- salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
- Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydramine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
- basic ion exchange resins such as arg
- salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
- acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
- Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
- references to the compounds of Formula I to XXV-B are meant to also include the pharmaceutically acceptable salts.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- an oil medium for example peanut oil, liquid paraffin, or olive oil.
- Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorb
- the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
- preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
- flavoring agents such as sucrose, saccharin or aspartame.
- sweetening agents such as sucrose, saccharin or aspartame.
- Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
- Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
- a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
- the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
- Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
- the emulsions may also contain sweetening and flavouring agents.
- Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
- the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butane diol.
- Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono-or diglycerides.
- fatty acids such as oleic acid find use in the preparation of injectables.
- the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an I atomizer using electrohydrodynamics to produce a fine mist) , or nebulizer, with or without the use of a suitable propellant, such as 1, 1, 1, 2-tetrafluoroethane or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane.
- the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
- the pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
- a solution or suspension of the compound (s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active, a propellant (s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
- the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) .
- This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
- Capsules (made, for example, from gelatin or HPMC) , blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
- the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
- Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
- a suitable solution formulation for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from log to 20mg of the compound of the invention per actuation and the actuation volume may vary from 11 to 1001.
- a typical formulation may comprise a compound of Formula I to XXV-B propylene glycol, sterile water, ethanol and sodium chloride.
- Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
- Suitable flavors such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
- Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly (DL-lactic-coglycolic acid (PGLA) .
- Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
- the dosage unit is determined by means of a valve which delivers a metered amount.
- Units in accordance with the invention are typically arranged to administer a metered dose or "puff" containing from 1 fig to 10 mg of the compound of Formula I to XXV-B.
- the overall daily dose will typically be in the range 1 lag to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
- Compounds of Formula I to XXV-B may also be administered in the form of suppositories for rectal administration of the drug.
- These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
- Such materials are cocoa butter and polyethylene glycols.
- creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I to XXV-B are employed.
- topical application shall include mouth washes and gargles.
- Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
- a condition may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
- the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
- Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
- Compounds of the present invention may be used to treat diseases with KRAS G12D mutant and the disease is any forms of cancer.
- the KRAS G12D mutant inhibitors disclosed herein can be combined with other cancer treatments.
- the inhibitors can be administered in combination with surgical treatments, radiation, or other therapeutic agents such as antibodies, kinase inhibitors, a target therapy, an inhibitor of MAP kinase signaling pathway, or chemotherapeutics.
- the inhibitors may also be administered in combination with RNAi therapy, antisense therapy, or immunotherapies.
- the KRAS G12D mutant inhibitors described herein may be combined with one, two, or more other therapeutic agents.
- second therapeutic agent also includes more than one therapeutic agent other than the KRAS G12D mutant inhibitor.
- the compounds disclosed herein may be combined with an agent such as sorafenib, a KRAS G12C inhibitor, a SOS1 inhibitor, a SHP2 inhibitor, a MEK inhibitor, a FAK kinase inhibitor, an EGFR inhibitor, an Aurora A inhibitor, a PD-1 antibody or a PD-L1 antibody.
- an agent such as sorafenib, a KRAS G12C inhibitor, a SOS1 inhibitor, a SHP2 inhibitor, a MEK inhibitor, a FAK kinase inhibitor, an EGFR inhibitor, an Aurora A inhibitor, a PD-1 antibody or a PD-L1 antibody.
- a KRAS G12D mutant inhibitor described herein may be administered with one, two, or more other therapeutic agents.
- the compounds of the present invention can be prepared according to the following synthetic schemes:
- SNU-1 (KRAS G12D) cancer cell line was obtained from ATCC (American Type Culture Collection, VA) . Cells were plated in 384-well plate in RPMI-1640 with 1%FBS. Serial dilution of compounds was made. The compounds at various concentrations and DMSO were added to the wells and incubated with cells for 4 days at 37°C. Cell viability was then determined by CellTiter-Glo (Promega, WI) .
- Phospho-ERK (pERK) assay SNU-1 cells were seeded in RPMI-1640 with 1%FBS 16 hours prior to compound treatment. Serial dilution of compounds was made and added to cells, and then incubated at 37°C for 3 hours. Cells (mostly in suspension) were collected and centrifuged. Cell pellets were washed with ice cold PBS, centrifuged, and lysed on ice with a lysis buffer containing 25 mM HEPES (pH 7.2-7.5) , 150 mM NaCl, 1%Triton X-100 and 10%glycerol.
- the lysis buffer was supplemented with protease inhibitor and phosphatase inhibitor cocktails (Sigma-Aldrich) and 1 mM DTT before use.
- Cell lysates were centrifuged, and the supernatants were collected for evaluation of pERK level. Equal amounts of proteins from the supernatants were loaded onto 4-12%Criterion XT Bis-Tris Precast Gels (Bio-Rad) . After electrophoresis and transfer to the nitrocellulose membrane (Bio-Rad) , the western blotting was performed following the standard protocol with anti-pERK1/2 antibody (Cell Signaling Technology) and anti-rabbit IgG HRP-linked secondary antibody (Cell Signaling Technology) .
- the chemiluminescence was developed using Clarity Western ECL Substrate (Bio-Rad) .
- the chemiluminescent densities of the pERK bands were captured and analyzed by ChemiDoc and Image Lab software (Bio-Rad) according to manufacturer's instruction.
- IC 50 values of compounds were determined as the concentration of 50%inhibition of cell viability or pERK level compared to DMSO treated cells (A: IC 50 ⁇ 0.2 ⁇ M; B: IC 50 between 0.2 ⁇ M and 0.5 ⁇ M; C: between 0.5 ⁇ M and 5 ⁇ M; D: IC 50 > 5 ⁇ M) .
- Some compounds of the present invention have IC 50 between 0.2 ⁇ M to 5 ⁇ M or > 5 ⁇ M, and surprisingly some compounds of the present invention have IC 50 ⁇ 0.2 ⁇ M.
- CIP means 2-chloro-1, 3-dimethylimidazolidinium hexafluorophosphate
- EA means ethyl acetate
- DBU means l, 8-diazabicyclo [5.4.0] undec-7-ene
- DIBAL means diisobutylaluminum hydride
- DIPEA means diisopropylethylamine
- DMAP means N, N-dimethylaminopyridine
- DME means 1, 2-dimethoxyethane
- DMF means N, N-dimethylformamide
- dmpe means l, 2-bis (dimethyl ⁇ hosphino) ethane
- DMSO means dimethylsulfoxide
- dppb means l, 4-bis (diphenylphosphino) butane
- dppe means 1, 2-bis (diphenylphosphino) ethane
- dppf means 1, 1’-bis(diphenylphosphino)
- HPLC-MS analyses were performed on Waters HPLC 2790 with Waters micromass ZQ 4000 (Model MAA050) as mass detector and Waters 2487 UV as detector. Column used was Phenomemex OOB-4605-E0 (5u-XB-C18-100A, 50 x4.6mm) .
- the mobile phase consists eluent A (water, 0.05%TFA) and eluent B (CH3CN, 0.05%TFA) , and the elution proceeded at 1 mL/min.
- the initial conditions were 90%A for 1 min, then 90%A to 10%A linearly decreased within 5 min, then from 10%A to 90%A within 1 min.
- the total run time is 7 minutes.
- Step 8 ( ⁇ ) tert-butyl 3- (trifluoromethylsulfonyloxy) -8-azabicyclo [3.2.1] oct-3-ene-8-carboxylate
- Step 13 3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-ol
- Step 14 3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl trifluoromethanesulfonate
- Step 15 triisopropyl ( (6- (methoxymethoxy) -8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) naphthalen-1-yl) ethynyl) silane
- Step 17 2- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane
- Step 18 ( ⁇ ) tert-butyl 3- (7- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (hexahydro-1H-pyrrolizin-7a-yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -8-azabicyclo [3.2.1] oct-3-ene-8-carboxylate
- Step 19 4- (4- (8-azabicyclo [3.2.1] oct-3-en-3-yl) -8-fluoro-2- ( (hexahydro-1H-pyrrolizin-7a-yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol
- Step 3 di-tert-butyl 7- (7- (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-4-yl) -3, 7, 9-triazabicyclo [3.3.1] nonane-3, 9-dicarboxylate
- Step 4 4- (4- (3, 7, 9-triazabicyclo [3.3.1] nonan-3-yl) -8-fluoro-2- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethylnaphthalen-2-ol
- Step 1 8-fluoro-7- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4, 3-d] pyrimidine-2, 4-diol
- Step 2 4-dichloro-8-fluoro-7- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) pyrido [4, 3-d] pyrimidine
- Step 5 N- (1, 7-dichloro-4- ( (trimethylsilyl) ethynyl) heptan-4-yl) -2-methylpropane-2-sulfinamide
- Step 6 7-dichloro-4- ( (trimethylsilyl) ethynyl) heptan-4-amine
- Step 7 7a- ( (trimethylsilyl) ethynyl) hexahydro-1H-pyrrolizine
- Step 12 4- (4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (E) -2- (tetrahydro-1H-pyrrolizin-7a (5H) -yl) vinyl) pyrido [4, 3-d] pyrimidin-7-yl) -5-ethynylnaphthalen-2-ol
- Step 2 tert-butyl 3- (3-chloro-6- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalene-1-yl) -2, 7-naphthyridin-1-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate &tert-butyl (1R, 5S) -3- (6-chloro-3- (3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) -2, 7-naphthyridin-1-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 5 (8- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -6- ( (hexahydro-1H-pyrrolizin-7a-yl) methoxy) -2, 7-naphthyridin-3-yl) -5-ethynylnaphthalen-2-ol
- Step 1 tert-butyl 3- (6-chloro-3- ( (tetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -2, 7-naphthyridin-1-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate &tert-butyl 3- (3-chloro-6- ( (hexahydro-1H-pyrrolizin-7a-yl) methoxy) -2, 7-naphthyridin-1-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 4 4- (1- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -6- ( (hexahydro-1H-pyrrolizin-7a-yl) methoxy) -2, 7-naphthyridin-3-yl) -5-ethynylnaphthalen-2-ol
- Step 2 ethyl 7-chloro-8-fluoro-2, 4-dihydroxy-1, 6-naphthyridine-3-carboxylate
- Step 3 7 -chloro-8-fluoro-1, 6-naphthyridine-2, 4-diol
- P2 was synthesized using the same procedures as described in the procedure of the synthesis of P1 of step 5.
- P2A was synthesized using the same procedures as described in the procedure of the synthesis of P1 of step 6 .
- Step 7 4- (4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -8-fluoro-2- ( (hexahydro-1H-pyrrolizin-7a-yl) methoxy) -1, 6-naphthyridin-7-yl) -5-ethylnaphthalen-2-ol
- Step 4 ethyl 6-chloro-4- (3- (2, 2, 2-trichloroacetyl) ureido) pyridazine-3-carboxylate
- Step 8 tert-butyl 3- (3-chloro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [5, 4-c] pyridazin-8-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 10 4- (8- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [5, 4-c] pyridazin-3-yl) -5-ethyl-6-fluoronaphthalen-2-ol
- Step 2 4- (8- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -6- ( ( (2R, 7aS) -2-fluorohexahydro-1H-pyrrolizin-7a-yl) methoxy) pyrimido [5, 4-c] pyridazin-3-yl) -5-ethylnaphthalen-2-ol
- Step 5 (8-ethyl-3- (methoxymethoxy) naphthalen-1-yl) boronic acid
- Step 6 5- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (8-ethyl-3-hydroxynaphthalen-1-yl) -7- ( ( (2S, 7aR) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 4-d] pyridazin-1 (2H) -one
- Step 1 (7-fluoro-3- (methoxymethoxy) -8- ( (triisopropylsilyl) ethynyl) naphthalen-1-yl) boronic acid
- Step 4 5- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -2- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -7- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrido [3, 4-d] pyridazin-1 (2H) -one
- Step 7 tert-butyl 3- (7- (8-ethynyl-7-fluoro-3- (methoxymethoxy) naphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) -8-oxo-7, 8-dihydropyrimido [4, 5-d] pyridazin-4-yl) -3, 8-diazabicyclo [3.2.1] octane-8-carboxylate
- Step 8 4- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -7- (8-ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl) -2- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [4, 5-d] pyridazin-8 (7H) -one
- Step 3 4- (8- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [5, 4-c] pyridazin-3-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
- step 2 To a stirred solution of the product of step 1 cooled at -78°C is added n-BuLi dropwise. After stirring for 30 min, N-fluorobenzenesulfonimide is added to the mixture. Normal work-up and purification afford the title product of step 2. MS (ES+) : 552 [M+1] + .
- Step 5 4- (8- (3, 8-diazabicyclo [3.2.1] octan-3-yl) -4-fluoro-6- ( ( (2R, 7aS) -2-fluorotetrahydro-1H-pyrrolizin-7a (5H) -yl) methoxy) pyrimido [5, 4-c] pyridazin-3-yl) -5-ethynyl-6-fluoronaphthalen-2-ol
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Abstract
L'invention concerne des hétérocycles utilisés en tant qu'inhibiteurs de KRAS G12D, en particulier un composé de formule I ou un sel pharmaceutiquement acceptable de celui-ci, et une composition pharmaceutique comprenant ledit composé qui sont utiles pour le traitement de maladies et d'états pathologiques médiés par KRAS G12D, tels que le cancer.
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Cited By (9)
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WO2023056951A1 (fr) * | 2021-10-08 | 2023-04-13 | 杭州德睿智药科技有限公司 | Composé hétérocyclique substitué par aryle |
WO2023061294A1 (fr) * | 2021-10-13 | 2023-04-20 | 再鼎医药(上海)有限公司 | Régulateur dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation |
WO2023061463A1 (fr) * | 2021-10-15 | 2023-04-20 | 广东东阳光药业有限公司 | Nouveau composé de pyrimidopyridine, composition pharmaceutique de celui-ci et utilisation associée |
WO2023114733A1 (fr) * | 2021-12-13 | 2023-06-22 | Quanta Therapeutics, Inc. | Modulateurs de kras et leurs utilisations |
WO2023134465A1 (fr) * | 2022-01-11 | 2023-07-20 | 上海艾力斯医药科技股份有限公司 | Composé hétérocyclique contenant de l'azote, son procédé de préparation, intermédiaire de celui-ci et utilisation associée |
WO2023138583A1 (fr) * | 2022-01-21 | 2023-07-27 | 上海湃隆生物科技有限公司 | Composé hétérocyclique, composition pharmaceutique et utilisation associée |
US11912723B2 (en) | 2022-02-09 | 2024-02-27 | Quanta Therapeutics, Inc. | KRAS modulators and uses thereof |
WO2024054926A1 (fr) * | 2022-09-07 | 2024-03-14 | Bristol-Myers Squibb Company | Inhibiteurs de kras g12d |
WO2024078555A1 (fr) * | 2022-10-13 | 2024-04-18 | 广东东阳光药业股份有限公司 | Composé pyrimidopyridine, composition pharmaceutique et leur utilisation |
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