WO2024027792A1 - Protein kinase degrading agent, medicament and use - Google Patents
Protein kinase degrading agent, medicament and use Download PDFInfo
- Publication number
- WO2024027792A1 WO2024027792A1 PCT/CN2023/110961 CN2023110961W WO2024027792A1 WO 2024027792 A1 WO2024027792 A1 WO 2024027792A1 CN 2023110961 W CN2023110961 W CN 2023110961W WO 2024027792 A1 WO2024027792 A1 WO 2024027792A1
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- WO
- WIPO (PCT)
- Prior art keywords
- piperidin
- independently
- phenyl
- ethynyl
- pyridazin
- Prior art date
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- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 235000020183 skimmed milk Nutrition 0.000 description 1
- 108010026668 snake venom protein C activator Proteins 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- SJMDMGHPMLKLHQ-UHFFFAOYSA-N tert-butyl 2-aminoacetate Chemical compound CC(C)(C)OC(=O)CN SJMDMGHPMLKLHQ-UHFFFAOYSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- RMWVUWLBLWBQDS-UHFFFAOYSA-N tert-butyl 3-bromopropanoate Chemical compound CC(C)(C)OC(=O)CCBr RMWVUWLBLWBQDS-UHFFFAOYSA-N 0.000 description 1
- GNDQONYTPMGMTM-UHFFFAOYSA-N tert-butyl n-[2-[2-[2-(2-bromoethoxy)ethoxy]ethoxy]ethyl]carbamate Chemical compound CC(C)(C)OC(=O)NCCOCCOCCOCCBr GNDQONYTPMGMTM-UHFFFAOYSA-N 0.000 description 1
- CKXZPVPIDOJLLM-UHFFFAOYSA-N tert-butyl n-piperidin-4-ylcarbamate Chemical compound CC(C)(C)OC(=O)NC1CCNCC1 CKXZPVPIDOJLLM-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
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- 102000027257 transmembrane receptors Human genes 0.000 description 1
- 108091008578 transmembrane receptors Proteins 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical compound C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- 108010064892 trkC Receptor Proteins 0.000 description 1
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Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/05—Dipeptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention belongs to the field of biomedical technology, and is directed to a compound useful as protein kinase degrading agent, pharmaceutical composition comprising the same and use thereof.
- Protein kinase is a category of phosphoacyltransferases with relavant the structural formulae, which has a highly conservative structure and catalytic function, and is distributed throughout the nucleus, mitochondria, microsome and cytosol in cells. Protein kinases play a crucial role in regulating cell growth and differentiation, responsible for controlling various cell transduction processes. The overexpression or inappropriate expression of normal or mutated protein kinases is crucial in the development of various diseases and conditions.
- Tropomyosin receptor kinase is a transmembrane receptor tyrosine kinase on the cell surface, mainly including subtypes of TRKA, TRKB and TRKC which are encoded by NTRK1, NTRK2 and NTRK3 genes respectively.
- NTRK gene fusion occurs due to chromosomal variation, it leads to the phosphorylation of TRK kinase and the activation of downstream signaling pathways, thereby regulating cell growth, differentiation, invasion, migration, apoptosis and so on.
- TRK inhibitors currently on the market include selective TRKA/B/C inhibitor larotrectinib and inhibitor entrectinib which simultaneously has multiple targets of kinase inhibitory activity such as ALK, ROS1, and TRKs. These two drugs have provided good therapeutic effects for patients with tumor carrying NTRK fusion. However, when the drugs are coming into use, clinical drug-resistant mutations followed, such as the solvent front point mutation TRKAG595R and TRKCG623R, xDFG mutations TRKAG667C and TRKAG667A, and so on.
- PROTAC proteolysis-targeting chimeras
- proteolysis-targeting chimeras is a technology using the ubiquitin proteasome system to degrade target proteins, wherein by degrading target proteins or mutant proteins of target proteins, molecules disable the function of the target proteins.
- the present invention aims to provide a novel protein kinase degrading compound.
- the present invention aims at providing a protein kinase degrading agent, pharmaceutical composition comprising the same and use thereof, so as to solve the above-mentioned problems in the existing method.
- said protein kinase is TRK.
- said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
- the first aspect is a first aspect:
- the present invention provides a compound, said compound is a compound having a chemical structure of general Formula (I) :
- said E3ubiquitin ligase is selected from the group consisting of CRBN (Celebron) or vHL (von Hippel-Lindau)
- the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof
- the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
- L is a linker
- said tropomyosin-related kinase ligand is selected from the group consisting of a protein kinase inhibitor or a protein kinase inhibitor fragment, said tropomyosin-related kinase ligand functions at least via the binding to one of protein kinase, protein kinase mutation, protein kinase fusion and protein kinase deletion.
- the E3 ubiquitin ligase ligand is attached to the left side of L and the protomyosin-associated kinase ligand is attached to the right side of L.
- the present invention is further directed to a compound of Formula (A) or a pharmaceutically acceptable salt thereof:
- A is E3 ubiquitin ligase ligand selected from the group consisting of CRBN or vHL, the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
- x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
- y at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
- z at each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
- the left-most O is optionally replaced by NH
- the right-most O is optionally replaced by NH
- one or more (e.g., 1, 2, 3, or 4) O of (O (CH 2 ) y ) z is optionally replaced by NH
- one CH 2 of - (CH 2 ) x are optional
- the present invention is further directed to a compound of Formula (B) or a pharmaceutically acceptable salt thereof:
- A is E3 ubiquitin ligase ligand selected from the group consisting of CRBN or vHL, the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
- the present invention is further directed to a compound of Formula (C) or a pharmaceutically acceptable salt thereof:
- A is E3 ubiquitin ligase ligand selected from the group consisting of CRBN or vHL, the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
- said tropomyosin-related kinase ligand has a chemical structure of general Formula (II) :
- R 1 is H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or halogen substituted C 1 -C 6 alkyl
- R 2 is H, fluoro-substituted C 1 -C 4 alkyl, or substituted or unsubstituted 5-6 membered heterocyclyl containing 1-3 N ring atoms
- R 3 is H, halogen, amino or C 1 -C 3 alkyl substituted amino, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 1 -C 10 alkoxy, substituted or unsubstituted 5-10 membered heterocyclyl containing 1-3 N ring atoms, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 N ring atoms
- R 4 is C 1 -C 6 alkyl
- R 5 is -NR 6 R 7 , wherein, each of R 6 and R 7 is independently selected from the group consisting of: - (CH 2 ) m NR 8 R 9 , - (CH 2 ) n CR 10 R 11 R 12 , - (CH 2 ) p OR 12 , or R 6 and R 7 together with the nitrogen atom to which they attach to form a substituted or unsubstituted heteroatom-containing monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring; each of R 8 and R 9 is independently selected from the group consisting of: H, C 1 -C 20 alkyl; or R 8 and R 9 together with the nitrogen atom to which they attach to form a substituted or unsubstituted monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring containing 1-3 heteroatoms; R 10 and R 11 together with the carbon atom to which they attach to form a substituted or unsubstit
- said tropomyosin-related kinase ligand has a chemical structure of general Formula (II 1 ) :
- t is 1, 2 or 3
- X is H, Cl or Br.
- said tropomyosin-related kinase ligand is attached to L via a bond formed after removing the OH in Formula (II 1 ) .
- said tropomyosin-related kinase ligand has any of the following structures:
- said tropomyosin-related kinase ligand is attached to L via a bond formed after removing the OH or NH 2 in the above-mentioned structures.
- said tropomyosin-related kinase ligand is which is attached to L via a bond formed after removing the OH.
- said L has a chemical structure of general Formula (III) :
- Y 1 and Z 1 independently are O, S or NH
- W 1 and W 2 independently are absent, O, NH, C 1 -C 6 linear alkyl, or a 1 , b 1 , a 2 , b 2 , a 3 , and a 4 independently are positive integers of 0 to 20
- Q 1 , Q 2 , Q 3 , and Q 4 independently are -CH 2 -, NH, and O
- W 1 and W 2 independently are NH or linear alkyl, they are optionally substituted with hydroxy, C 1 - C 10 alkyl, C 1 -C 6 alkoxy, or halogen;
- said L has any of the following structures:
- said L has a chemical structure of general Formula (IV) :
- Y 2 and Z 2 are O, S or NH;
- W 3 , W 4 , and W 5 independently are absent, O, NH, C 1 -C 6 linear alkyl, or c, d, e, f, g, and h independently are positive integers of 0 to 20;
- M 1 and M 2 independently are -CH-or N;
- Q 4 , Q 5 , Q 6 , and Q 7 independently are -CH 2 -, NH, or O.
- said L has any of the following structures:
- said L has a chemical structure of general Formula (V) :
- Y 3 and Z 3 are O, S or NH; W 6 and W 7 are absent, O, NH, C 1 -C 6 linear alkyl, or i and n' independently are positive integers of 0-16; M 3 and M 4 of the spiro cyclic moiety independently are selected from the group consisting of NH or CH; j, k, l, and m' independently are selected from the group consisting of 0, 1, 2, 3; Q 8 and Q 9 independently are -CH 2 -, NH, or O.
- said L has any of the following structures:
- said C 1 -C 6 linear alkyl is selected from the group consisting of any of the following groups:
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-, wherein y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-, wherein z, at each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-, wherein the left-most O is optionally replaced by NH.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-, wherein the right-most O is optionally replaced by NH.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-, wherein one or more (e.g., 1, 2, 3, or 4) O of (O (CH 2 ) y ) z is optionally replaced by NH.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z -O-, wherein one CH 2 of - (CH 2 ) x -is optionally replaced by a piperazin-1, 4-diyl or a 7-to 11-membered saturated diazaspirocyclo-diyl (e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl) .
- a piperazin-1, 4-diyl or a 7-to 11-membered saturated diazaspirocyclo-diyl e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl
- said L is attached to the tropomyosin-related kinase ligand via the - (piperidin-1, 4-diyl) -O-comprised in L, wherein the piperidin-1, 4-diyl is attached to the left part at its position 1 and is attached to the right part at its position 4.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein z, at each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein the left-most O is optionally replaced by NH.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein the right-most O is optionally replaced by NH.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein one or more (e.g., 1, 2, 3, or 4) O of (O (CH 2 ) y ) z is optionally replaced by NH.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein the piperidin-1, 4-diyl is attached to the left part at its position 1 and is attached to the right part at its position 4.
- said L is -O- (CH 2 ) x - (O (CH 2 ) y ) z - (piperidin-1, 4-diyl) -O-, wherein one CH 2 of - (CH 2 ) x -is optionally replaced by a piperazin-1, 4-diyl or a 7-to 11-membered saturated diazaspirocyclo-diyl (e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl) .
- diazaspirocyclo-diyl e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl
- said L is (piperidin-1, 4-diyl) - (CH 2 ) x - (piperidin-1, 4-diyl) - (CH 2 ) y - (piperidin-1, 4-diyl) -O-.
- said L is (piperidin-1, 4-diyl) - (CH 2 ) x - (piperidin-1, 4-diyl) - (CH 2 ) y - (piperidin-1, 4-diyl) -O-, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is (piperidin-1, 4-diyl) - (CH 2 ) x - (piperidin-1, 4-diyl) - (CH 2 ) y - (piperidin-1, 4-diyl) -O-, wherein y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
- said L is (piperidin-1, 4-diyl) - (CH 2 ) x - (piperidin-1, 4-diyl) - (CH 2 ) y - (piperidin-1, 4-diyl) -O-, wherein each of the piperidin-1, 4-diyls is attached to the left part at its position 1 and is attached to the right part at its position 4.
- said L is
- said L is
- E3 ubiquitin ligase ligand VH032
- Lenalidomide Lenalidomide
- Pomalidomide Hermandidomide
- Thalidomide has the following structures, respectively.
- VH032 is attached to L via a bond formed after removing the acetyl in its structure.
- Lenalidomide and Pomalidomide are attached to L via a bond formed after removing the NH 2 in their structures.
- Thalidomide is attached to L via a bond formed after removing the H at position 4 or 5 of its 1, 3-dioxoisoindoline.
- any of the following compounds is included:
- said compound is the title compound of any of Examples 1-38.
- said compound is the title compound of any of Examples 5, 9, 11, 12, 25, 26, and 33.
- said compound further includes: a pharmaceutically acceptable salt, stereisomer, ester, prodrug, solvate and deuterated compound of said compound.
- said compound is a protein kinase degrading agent.
- said protein kinase is TRK.
- said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
- the present invention further provides a pharmaceutical composition comprising the above-mentioned compound.
- said protein kinase is TRK.
- said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
- the present invention further provides use of the above-mentioned compound useful as a protein kinase degrading agent or the above-mentioned pharmaceutical composition in the manufacture of a medicament for the prevention, diagonosis or treatment of protein kinase mediated diseases caused by the expression, mutation or fusion of a protein kinase.
- said protein kinase is TRK.
- said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
- said protein kinase mediated disease is tumor including at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
- the administration route of said medicament includes at least one of oral, intracutaneous injection, subcutaneous injection, application onto skin, parenteral, and rectal administration.
- the present invention further provides a method for the prevention, diagonosis or treatment of protein kinase mediated diseases caused by the expression, mutation or fusion of a protein kinase, said method comprising administering the above-mentioned compound useful as a protein kinase degrading agent to a subject in need thereof.
- said protein kinase is TRK.
- said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
- said protein kinase mediated disease is tumor including at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
- the present invention further provides the above-mentioned compound useful as a protein kinase degrading agent, for use of the prevention, diagonosis or treatment of protein kinase mediated diseases caused by the expression, mutation or fusion of a protein kinase.
- said protein kinase is TRK.
- said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
- said protein kinase mediated disease is tumor including at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
- alkyl refers to saturated or unsaturated, linear, branched or cyclic alkyl carbon chain with up to 10 carbon atoms.
- the linear alkyl includes, e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.
- the branched alkyl includes, e.g., isopropyl, sec-butyl, isobutyl, tert-butyl, neo-pentyl.
- the cycloalkyl includes, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- the unsaturated alkyl includes, e.g., alkyl carbon chain containing double bond, conjugated double bond, or triple bond.
- Alkyl may be substituted by one or more substituents, the non-limiting examples of the substituents include NH 2 , NO 2 , N (CH 3 ) 2 , ONO 2 , F, Cl, Br, I, OH, OCH 3 , CO 2 H, CO 2 CH 3 , CN, nitronyl, aryl and heteroaryl.
- alkyl also refers to unsubstituted or substituted linear, branched or cyclic alkyl containing a chain of up to 10 carbon atoms with at least one heteroatom (for instance, nitrogen, oxygen or sulfur) .
- the above-mentioned linear alkyl includes, for instance, CH 2 CH 2 OCH 3 , CH 2 CH 2 N (CH 3 ) 2 and CH 2 CH 2 SCH 3 .
- the branched groups include, for instance, CH 2 CH (OCH 3 ) CH 3 , CH 2 CH (N (CH 3 ) 2 ) CH 3 and CH 2 CH (OCH 3 ) CH 3 .
- the above-mentioned cyclic groups include, for instance, six-membered cyclic CH (CH 2 CH 2 ) 2 O, CH (CH 2 CH 2 ) 2 NCH 3 and CH (CH 2 CH 2 ) 2 S and the corresponding five-member ring, and the like.
- the above-mentioned alkyl may be substituted by one or more substituents.
- the non-limiting examples of the above-mentioned substituents include NH 2 , NO 2 , N (CH 3 ) 2 , ONO 2 , F, Cl, Br, I, OH, OCH 3 , CO 2 H, CO 2 CH 3 , CN, aryl and heteroaryl.
- aryl refers to substituted or unsubstituted aromatic compounds, carbocyclic groups and heteroaryl.
- Aryl is a monocyclic or is a polycyclic fused compound.
- phenyl is a monocyclic aryl.
- Naphthyl is an example with polycyclic fused aryl.
- Aryl may be substituted by one or more substituents, and the non-limiting examples of the substituents include NH 2 , NO 2 , N (CH 3 ) 2 , ONO 2 , F, Cl, Br, I, OH, OCH 3 , CO 2 H, CO 2 CH 3 , CN, nitronyl, aryl and heteroaryl.
- Heteroaryl is directed to substituted or unsubstituted monocyclic or polycyclic groups, ring members include at least one heteroatom, such as nitrogen, oxygen and sulfur.
- typical heterocyclyl includes one or more nitrogen atom, such as tetrazolyl, pyrrolyl, pyridinyl (e.g., 4-pyridinyl, 3-pyridinyl, 2-pyridinyl and the like) , pyridazinyl, indolyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, etc.
- Typical heterocyclyls containing one oxygen atom include 2-furanyl, 3-furanyl or benzofuranyl;
- Typical groups containing sulfur heteroatom include thienyl and benzothienyl;
- Typical groups containing mixed heteroatoms include furazanyl, oxazolyl, isooxazolyl, thiazolyl, and phenoxthinyl.
- Heterocyclic groups can be substituted by one or more substituents.
- substituents include NH 2 , NO 2 , O-alkyl, NH-alkyl, N (alkyl) 2 , NHC (O) -alkyl, ONO 2 , F, Cl, Br, I, OH, OCF 3 , OSO 2 CH 3 , CO 2 H, CO 2 -alkyl, CN, nitronyl, and aryl and polyaryl.
- These situations also include the oxidation of heteroatoms within the ring, such as the formation of N-oxides, ketones, or sulfones.
- the compound involved in the Examples of the present invention may be used a pharmaceutical active ingredient in a therapeutically effective amount for the preparation of a specific drug together with pharmaceutically acceptable carriers and excipients, for the prevention, diagonosis or treatment of a protein kinase mediated disease caused by the expression, mutation or fusion of a protein kinase.
- Said disease is preferably tumor, tumor includes at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
- the therapeutically effective amount refers to the dosage needed to achieve the therapeutical effect.
- the term “pharmaceutically acceptable” refers to the absence of unacceptable toxicity in compounds such as salts or excipients.
- Pharmaceutically acceptable salts include inorganic anions, such as chloride ion, bromine ion, iodine ion, sulfate ion, sulfite ion, nitrate ion, nitrite ion, phosphate ion, hydrogen phosphate ion, and the like.
- Organic anions include acetate ion, propionate ion, cinnamate ion, benzenesulfonate ion, citrate ion, lactate ion, gluconate ion, and the like.
- the pharmaceutically acceptable excipients are described in the following text.
- the compound of the Examples of the present invention can be made into various dosage forms, including solid dosage forms, semi-solid dosage forms, liquid dosage forms, and aerosols (Remington’s Pharmaceutical Sciences, Mack Publishing Company (1995) , Philade lphia, PA, 19th ed) .
- the specific dosage forms in these types of dosage forms include tablets, pills, lozenges, granules, gel, plasters, solutions, suppositories, injections, inhalants and sprays. These dosage forms can be used for both local or systemic administration as well as rapid or sustained release administration.
- There are many methods of administration for these drugs including oral administration, buccal administration, rectal administration, peritoneal administration, intraperitoneal administration, superficial administration, subcutaneous administration, and tracheal administration, and the like.
- the compound of the Examples of the present invention can be formulated into a solution, suspension, and emulsion using water-soluble or lipophilic solvents during injection administration.
- Lipophilic solvents specifically include vegetable oils and similar oils, synthetic fatty acid glycerides, higher aliphatic acid esters, and glycol esters (roylene glycol) , which are more readily soluble in Hank’s solution, Ringer’s solution, or physiological saturated NaCl aqueous solution.
- the compound in the Examples of the present invention when administered orally, it can be compounded with pharmaceutically acceptable excipients by common technical means in the art. These excipients can make these compounds into various dosage forms that can be used by patients, such as tablets, pills, suspensions, gel, and the like. There are various methods for preparing oral formulations, such as first mixing the compound and solid excipient, thoroughly grinding the mixture, adding appropriate excipients, and processing it into granules.
- excipients that can be used to make oral dosage forms include: sugars such as lactose, sucrose, mannitol or sorbitol; Cellulose, such as corn starch, wheat starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxyproylmethyl-cellulose, methyl cellulose sodium, polyvinyl pyrrolidone, and the like.
- the compound of the Examples of the present invention can also be made into a spray, which is realized through a pressurizer and a nebulizer or a dry powder inhalation device.
- Suitable injection agent that can be used in an injector includes, e.g., dichloro difluoromethane, fluorotrichloromethane, dichloro tetrafluoroethane, carbon dioxide and dimethyl ether.
- the dosage of aerosol administration can be adjusted through the valve of the injector.
- the various dosage forms of the compound of the Examples of the present invention are related to the therapeutically effective amount of the compound involved.
- the therapeutically effective amount of such groups of compounds depends on the patient receiving treatment. When determining the appropriate dosage, the patients’ weight, condition, medication regimen, and the subjective judgment of the prescription physicians should be taken into account.
- the therapeutically effective amount of the compounds and the derivatives thereof with multiple mechanisms of action should be determined by competent and experienced prescription physicians.
- the Examples of the present invention further include an additional treatment plan applied to patients with protein kinase mediated diseases, which includes surgical treatment and radiation therapy.
- Ba/F3 cell lines (Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C) were incubated at 37°C in an incubator under 5%CO 2 . Regularly subcultured, cells in the logarithmic growth phase were taken for planking. Cells were stained with trypan blue and viable cells were counted, with a required cell viability rate of over 90%. The cell concentration was adjusted to an appropriate concentration. 95 ⁇ L of the cell suspension was added to each well in the compound detection cell plate, culture solution without cell (containing 0.1%) was added to the Min control well and cultured for 24 hours. 5 ⁇ L of the 20 *compound working solution was taken to add to the cell culture plate.
- Inhibition Rate (Inh%) 100- (RLUDrug-RLUMin) / (RLUMax-RLUMin) *100%.
- the inhibition rate of the compound against the proliferation of Ba/F3 cells containing NTRK fusion and fusion mutation is provided at the end of each of the corresponding Examples.
- Ba/F3-LMNA-NTRK1-G667C cells were cultured to a coverage of 60-70%, added with corresponding concentrations of the compounds, and cultured for 24 hours; after centrifuging at 8000 rpm for 3 minutes, cells were collected and added 68 ⁇ l of ice-bathed RIPA lysis solution. It was mixed and allowed to stand on ice for 30 minutes. Every 10 minutes, it was vortexed and reversed to fully lyse, and centrifuged and then placed on ice.
- the PVDF film was placed in a 5%skimmed milk blocking solution for 1 hour, and slowly washed 3 times in TBST for 10 minutes each time. The washed PVDF film was then placed in a box containing the first antibody and incubated in a shaking bed at 4°C for 10-16 hours. The PVDF film was then taken out and slowly washed in TBST for 3 times, then added the secondary antibody and incubated at room temperature for 1 hour. After completion, the PVDF film was removed and washed with TBST for three times. The color developing solutions were mixed, evenly added to the surface of the film, exposed and developed in the Tanon 5200 luminescent imager, and photos were taken to save the image.
- TRK degradation rate of Ba/F3-LMNA-NTRK1-G667C cells treated with the compound is provided at the end of each of the corresponding examples.
- DIEA N, N-diisopropylethylamine
- HATU 2- (7-azabenzotriazol) -N, N, N', N'-tetramethylurea hexafluorophosphate
- NMP N-methylpyrrolidinone
- PE petroleum ether
- Ph phenyl
- TEA triethylamine
- TFA trifluoroacetic acid
- Example 1 1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamido) butyl) carbamate
- Example 1 The title compound of Example 1 was synthesized according to the synthetic route as shown below.
- Step 3 Methyl 3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzoate (1-3)
- Step 4 3- ( (6-Chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzoic acid (1-4)
- the organic phase from the first and the second extraction was combined and washed with saturated NaCl aqueous solution (200mL) , dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to provide a residue.
- the residue was slurried with MeOH (20mL) and filtered to provide the product 1-4 (2.00g, 6.42mmol, yield: 80.4%) , as a yellow solid.
- MS (ESI) m/z: 312.1 [M+H] + .
- Step 5 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (1-5)
- Step 6 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4-hydroxypiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (1-6)
- Step 7 1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4-nitrophenyl) carbonate (1-7)
- Step 8 tert-Butyl 2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxyacetate (1-8)
- Step 9 2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetic acid (1-9)
- Step 10 tert-Butyl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamido) butyl) carbamate (1-10)
- Step 11 N- (4-Aminobutyl) -2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamide (1-11)
- Step 12 1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamido) butyl) carbamate
- reaction mixture was directly purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the product (28.7mg, 0.0292mmol, yield: 21.0%) , as a white solid.
- the inhibition rate of the title compound of Example 1 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was >90%.
- Step 1 6- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoic acid (2-1)
- Step 2 tert-Butyl 4- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-carboxylate (2-2)
- Step 3 N- (3-Chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (2-3)
- Step 4 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the resulting mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was poured into water (20mL) and the aqueous phase was extracted with EtOAc (20mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to provide a residue.
- the crude product was purified by preparative HPLC (mobile phase: acetonitrile-water, 0.1%TFA) , and then washed with saturated sodium bicarbonate aqueous solution (30mL) to provide the product (25.0mg, 0.0234mmol, yield: 13.7%) , as a yellow solid.
- the inhibition rate of the title compound of Example 2 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was >90%.
- Example 3 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -dioxoisoindolin-4-yl) amino) -3-oxopropoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- benzyl 4- (2- (2-hydroxyethoxy) ethoxy) piperidin-1-carboxylate 400mg, 1.24mmol was dissolved in DMF (2mL) and the mixture was placed in iced water bath, to which NaH (99mg, 60%w/w, 2.47mmol) was added. After being stirred for 30 min, tert-butyl 3-bromopropionate (518mg, 2.48mmol) was added. The reaction mixture was naturally warmed up to room temperature and stirred for 16 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (50mL*3) .
- the inhibition rate of the title compound of Example 3 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were >90%and >90%, respectively.
- reaction mixture was diluted with water (10mL) and extracted with EtOAc (20mL*3) .
- the organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to provide a residue.
- the residue was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) , so as to provide the target final product (21.0mg, 0.0208mmol, yield: 11.5%) , as a yellow solid.
- the inhibition rate of the title compound of Example 4 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.6%and 99.7%, respectively.
- the TRK degradation rate of Ba/F3-LMNA-NTRK1-G667C cells after being treated with the title compound of Example 4 at a concentration of 0.10 ⁇ M was 60.16%.
- reaction mixture was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target final product (25.9mg, 0.0263mmol, yield: 22.1%) , as a yellow solid.
- the inhibition rate of the title compound of Example 5 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were >90%and >90%, respectively.
- the TRK degradation rate of Ba/F3-LMNA-NTRK1-G667C cells after being treated with the title compound of Example 5 at a concentration of 0.10 ⁇ M was 86.08%.
- Example 6 1- (3- (3- (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) acetamido) butyl) carbamate
- the inhibition rate of the title compound of Example 6 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was >90%.
- Example 7 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- Step 1 tert-Butyl (3- (4- ( (1- (3- ( (3- (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -3-oxopropyl) carbamate
- Step 2 3- ( (6- (4- ( (1- (3-Aminopropionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
- Step 3 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 7 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 98.7%and 99.5%, respectively.
- Example 8 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyryl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 8 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.5%and 99.8%, respectively.
- the inhibition rate of the title compound of Example 9 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.9%and 99.8%, respectively.
- Example 10 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) butyryl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 10 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 88.3%and 99.1%, respectively.
- Example 11 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (1- ( (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) piperidin-4-yl) methyl) piperidin-4-carbonyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 11 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.2%and 99.1%, respectively.
- Example 12 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (2- (6- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) acetyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 12 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.7%and 99.1%, respectively.
- Example 13 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) piperidin-4-yl) acetyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 13 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 97.2%.
- Example 14 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- Step 1 tert-Butyl (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) carbamate (14-1)
- Step 2 3- ( (6- (4-Aminopiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
- tert-butyl (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) carbamate (2.5 g, 3.82 mmol) was dissolved in DCM (10.0 mL) , and then TFA (10.0 mL) was added. The mixture was stirred at room temperature and reacted for 3 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure.
- Step 3 tert-Butyl 4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyrate
- Step 4 4- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyric acid
- Step 5 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 14 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 98.7%and 99.0%, respectively.
- Example 15 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 15 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 98.9%.
- Example 16 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (5- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) pentanamido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 16 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 71.9%and 98.8%, respectively.
- Example 17 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 17 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 94.6%and 98.9%, respectively.
- Example 18 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 18 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.0%and 99.4%, respectively.
- Example 19 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (3- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) propoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 19 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 98.9%and 99.0%, respectively.
- Example 20 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (5- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) ethoxy) pentanamido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 20 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.4%and 99.4%, respectively.
- Example 21 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- Step 1 tert-Butyl 4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentyl) oxy) piperidin-1-carboxylate
- Step 2 2- (2, 6-Dioxopiperidin-3-yl) -4- ( (5- (piperidin-4-yloxy) pentyl) oxy) isoindolin-1, 3-dione
- Step 3 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 21 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 99.7%.
- Example 22 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 22 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 98.0%.
- Example 23 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (9- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) nonyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- Example 24 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- Step 1 4- ( (7-Bromoheptyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione
- Step 2 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 24 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 90.8%and 99.7%, respectively.
- Example 25 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) heptyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 25 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.6%and 99.4%, respectively.
- Example 26 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 26 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.9%and 99.3%, respectively.
- Example 27 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 27 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.2%and 99.1%, respectively.
- Example 28 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (2- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethyl) amino) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- Step 1 3- ( (6- (4- ( (2- (2- (2- (2- (2- (2-Bromoethoxy) ethoxy) ethoxy) ethyl) amino) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
- Step 2 tert-Butyl (2- (2- (2- (2-bromoethoxy) ethoxy) ethyl) (1- (3- ( (3- ( (3-chloro-5-trifluoromethylphenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) carbamate
- Step 3 tert-Butyl (1- (3- ( (3- ( (3-chloro-5-trifluoromethylphenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethyl) carbamate
- Step 4 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (2- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethyl) amino) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 28 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 98.6%.
- Example 29 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- ( (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethyl) amino) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 29 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 98.8%.
- Example 30 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- ( (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethyl) amino) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 30 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 98.7%.
- the inhibition rate of the title compound of Example 31 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M was 98.0%.
- Example 32 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethyl) piperazin-1-yl) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 32 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 98.8%and 98.8%, respectively.
- Example 33 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) piperazin-1-yl) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 33 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.8%and 99.4%, respectively.
- Example 34 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (9- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoindolin-4-yl) amino) ethyl) -3, 9-diazaspiro [5.5] undecan-3-yl) -2-oxoethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- Step 1 Ethyl 2- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) acetate
- Step 2 2- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) acetic acid
- Step 3 tert-Butyl 9- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -3, 9-diazaspiro [5.5] undecan-3-carboxylate
- Step 4 4- ( (2- (3, 9-Diazaspiro [5.5] undecan-3-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione
- Step 5 N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (9- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoindolin-4-yl) amino) ethyl) -3, 9-diazaspiro [5.5] undecan-3-yl) -2-oxoethoxy) piperidin-1- yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
- the inhibition rate of the title compound of Example 34 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 99.0%and 98.7%, respectively.
- Step 1 Methyl 8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctoate
- Step 2 8- ( ( (S) -1- ( (2S, 4R) -4-Hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctanoic acid
- the aqueous phase was extracted with EtOAc (80mL*3) .
- the organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na 2 SO 4 , filtered and then concentrated under reduced pressure.
- Step 3 (2S, 4R) -1- ( (S) -2- (8- (4- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -8-oxooctanamido) -3, 3-dimethylbutyramido) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
- N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (84.8 mg, 0.13 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na 2 SO 4 , filtered and then concentrated under reduced pressure.
- the inhibition rate of the title compound of Example 35 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 89.2%and 99.5%, respectively.
- Example 36 (2S, 4R) -1- ( (S) -2- (9- (4- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -9-oxononylamido) -3, 3-dimethylbutyramido) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
- the inhibition rate of the title compound of Example 36 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 78.7%and 99.5%, respectively.
- Example 37 N 1 - (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) -N 9 - ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) nonandiamide
- Step 1 Methyl 9- ( (3- ( (1- (3- ( (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -9-oxononanoate
- Step 2 9- ( (3- ( (1- (3- ( (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -9-oxononanoic acid
- Step 3 N 1 - (3- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) -N 9 - ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) nonandiamide
- the inhibition rate of the title compound of Example 37 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 ⁇ M were 88.0%and 99.7%, respectively.
- Example 38 (2S, 4R) -1- ( (S) -2- (tert-Butyl) -16- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) -4, 12-dioxo-6-oxa-3, 9, 13-triazahexadecanoyl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
- Step 1 tert-Butyl (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) carbamate
- Step 2 3- ( (6- (4- (3-Aminopropoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
- Step 3 Ethyl 3- ( (tert-butoxycarbonyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) amino) propionate
- Step 4 3- ( (tert-Butoxycarbonyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) - 2-oxoethoxy) ethyl) amino) propanoic acid
- Step 5 tert-Butyl (3- ( (3- ( (1- (3- ( (3- ( (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -3-oxopropyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) carbamic acid
- Step 6 (2S, 4R) -1- ( (S) -2- (tert-Butyl) -16- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) -4, 12-dioxo-6-oxa-3, 9, 13-triazahexadecanoyl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
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Abstract
The present invention belongs to the field of biomedical technology, and is specifically directed to a compound useful as protein kinase degrading agent, pharmaceutical composition comprising the same and the use thereof. The compound useful as protein kinase degrading agent disclosed by the present invention is a compound of general Formula (I), or a pharmaceutically acceptable salt, stereisomer, ester, prodrug, solvate, or deuterated compound thereof. The pharmaceutical composition disclosed by the present invention comprises the compound useful as protein kinase degrading agent. The present invention further discloses the pharmaceutical use of the compound useful as protein kinase degrading agent.
Description
The present invention belongs to the field of biomedical technology, and is directed to a compound useful as protein kinase degrading agent, pharmaceutical composition comprising the same and use thereof.
Protein kinase (PK) is a category of phosphoacyltransferases with relavant the structural formulae, which has a highly conservative structure and catalytic function, and is distributed throughout the nucleus, mitochondria, microsome and cytosol in cells. Protein kinases play a crucial role in regulating cell growth and differentiation, responsible for controlling various cell transduction processes. The overexpression or inappropriate expression of normal or mutated protein kinases is crucial in the development of various diseases and conditions.
Tropomyosin receptor kinase (TRK) is a transmembrane receptor tyrosine kinase on the cell surface, mainly including subtypes of TRKA, TRKB and TRKC which are encoded by NTRK1, NTRK2 and NTRK3 genes respectively. When NTRK gene fusion occurs due to chromosomal variation, it leads to the phosphorylation of TRK kinase and the activation of downstream signaling pathways, thereby regulating cell growth, differentiation, invasion, migration, apoptosis and so on.
The TRK inhibitors currently on the market include selective TRKA/B/C inhibitor larotrectinib and inhibitor entrectinib which simultaneously has multiple targets of kinase inhibitory activity such as ALK, ROS1, and TRKs. These two drugs have provided good therapeutic effects for patients with tumor carrying NTRK fusion. However, when the drugs are coming into use, clinical drug-resistant mutations followed, such as the solvent front point mutation TRKAG595R and TRKCG623R, xDFG mutations TRKAG667C and TRKAG667A, and so on. PROTAC (proteolysis-targeting chimeras) is a technology using the ubiquitin proteasome system to degrade target proteins, wherein by degrading target proteins or mutant proteins of target proteins, molecules disable the function of the target proteins. The present invention aims to provide a novel protein kinase degrading compound.
In such connection, the present invention aims at providing a protein kinase degrading agent, pharmaceutical composition comprising the same and use thereof, so as to solve the above-mentioned problems in the existing method. Preferably, said protein kinase is TRK. Preferably, said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
The technical solutions of the present invention are as follows:
The first aspect:
In one technical solution of the first apsect, the present invention provides a compound, said compound is a compound having a chemical structure of general Formula (I) :
E3 ubiquitin ligase ligand-L-tropomyosin-related kinase ligand (Ⅰ) ;
In said E3 ubiquitin ligase ligand, said E3ubiquitin ligase is selected from the group consisting of CRBN (Celebron) or vHL (von Hippel-Lindau) , the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
L is a linker;
said tropomyosin-related kinase ligand is selected from the group consisting of a protein kinase inhibitor or a protein kinase inhibitor fragment, said tropomyosin-related kinase ligand functions at least via the binding to one of protein kinase, protein kinase mutation, protein kinase fusion and protein kinase deletion.
In the present disclosure, unless otherwise indicated, the E3 ubiquitin ligase ligand is attached to the left side of L and the protomyosin-associated kinase ligand is attached to the right side of L.
In one further technical solution of the first aspect, the present invention is further directed to a compound of Formula (A) or a pharmaceutically acceptable salt thereof:
wherein
A is E3 ubiquitin ligase ligand selected from the group consisting of CRBN or vHL, the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
with respect to -O- (CH2) x- (O (CH2) y) z-O-, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; z, at each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; the left-most O is optionally replaced by NH; the right-most O is optionally replaced by NH; one or more (e.g., 1, 2, 3, or 4) O of (O (CH2) y) z is optionally replaced by NH; one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) x are optionally substituted with oxo (=O) ; one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) y are optionally substituted with oxo (=O) ; and one CH2 of - (CH2) x-is optionally replaced by a piperazin-1, 4-diyl or a 7-to 11-membered saturated diazaspirocyclo-diyl (e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl) .
In one further technical solution of the first aspect, the present invention is further directed to a compound of Formula (B) or a pharmaceutically acceptable salt thereof:
wherein
A is E3 ubiquitin ligase ligand selected from the group consisting of CRBN or vHL, the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
with respect to -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; z, at each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; the left-most O is optionally replaced by NH; the right-most O is optionally replaced by NH; one or more (e.g., 1, 2, 3, or 4) O of (O (CH2) y) z is optionally replaced by NH; one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) x are optionally substituted with oxo (=O) ; one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) y are optionally substituted with oxo (=O) ; and one CH2 of - (CH2) x-is optionally replaced by a piperazin-1, 4-diyl or a 7-to 11-membered saturated diazaspirocyclo-diyl (e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl) .
In one further technical solution of the first aspect, the present invention is further directed to a compound of Formula (C) or a pharmaceutically acceptable salt thereof:
wherein
A is E3 ubiquitin ligase ligand selected from the group consisting of CRBN or vHL, the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;
with respect to - (CH2) x-and - (CH2) y-, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) x are optionally substituted with oxo (=O) ; and one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) y are optionally substituted with oxo (=O) .
Other technical solutions of the first aspect are described as follows:
In any of the above-metioned technical solutions of the first aspect, said tropomyosin-related kinase ligand has a chemical structure of general Formula (II) :
wherein, R1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy or halogen substituted C1-C6 alkyl; R2 is H, fluoro-substituted C1-C4 alkyl, or substituted or unsubstituted 5-6 membered heterocyclyl containing 1-3 N ring atoms; R3 is H, halogen, amino or C1-C3 alkyl substituted amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted 5-10 membered heterocyclyl containing 1-3 N ring atoms, or substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 N ring atoms; R4 is C1-C6 alkyl;
R5 is -NR6R7, wherein, each of R6 and R7 is independently selected from the group consisting of: - (CH2) mNR8R9, - (CH2) nCR10R11R12, - (CH2) pOR12, or R6 and R7 together with the nitrogen atom to which they attach to form a substituted or unsubstituted heteroatom-containing monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring; each of R8 and R9 is independently selected from the group consisting of: H, C1-C20 alkyl; or R8 and R9 together with the nitrogen atom to which they attach to form a substituted or unsubstituted monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring containing 1-3 heteroatoms; R10 and R11 together with the carbon atom to which they attach to form a substituted or unsubstituted monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring containing 1-3 heteroatoms; R12 is selected from the group consisting of: H or C1-C20 alkyl; each of m, n, and p is independently selected from the group consisting of integers of 0-10. Preferably, said tropomyosin-related kinase ligand is attached to L via a bond formed after removing the substituent on R5 in Formula (Ⅱ) .
In any of the above-metioned technical solutions of the first aspect, said tropomyosin-related kinase ligand has a chemical structure of general Formula (Ⅱ1) :
wherein, t is 1, 2 or 3, X is H, Cl or Br. Preferably, said tropomyosin-related kinase ligand is attached to L via a bond formed after removing the OH in Formula (Ⅱ1) .
In any of the above-metioned technical solutions of the first aspect, said tropomyosin-related kinase ligand has any of the following structures:
Preferably, said tropomyosin-related kinase ligand is attached to L via a bond formed after removing the OH or NH2 in the above-mentioned structures.
In any of the above-metioned technical solutions of the first aspect, said tropomyosin-related kinase ligand iswhich is attached to L via a bond formed after removing the OH.
In any of the above-metioned technical solutions of the first aspect, said L has a chemical structure of general Formula (Ⅲ) :
wherein, Y1 and Z1 independently are O, S or NH; W1 and W2 independently are absent, O, NH, C1-C6 linear alkyl, ora1, b1, a2, b2, a3, and a4 independently are positive integers of 0 to 20; Q1, Q2, Q3, and Q4 independently are -CH2-, NH, and O; when W1 and W2 independently are NH or linear alkyl, they are optionally substituted with hydroxy, C1-
C10 alkyl, C1-C6 alkoxy, or halogen;
denotes an attachement point.
In any of the above-metioned technical solutions of the first aspect, said L has any of the following structures:
In any of the above-metioned technical solutions of the first aspect, said L has a chemical structure of general Formula (Ⅳ) :
wherein, Y2 and Z2 are O, S or NH; W3, W4, and W5 independently are absent, O, NH, C1-C6 linear alkyl, orc, d, e, f, g, and h independently are positive integers of 0 to 20; M1 and M2 independently are -CH-or N; Q4, Q5, Q6, and Q7 independently are -CH2-, NH, or O.
In any of the above-metioned technical solutions of the first aspect, said L has any of the following structures:
In any of the above-metioned technical solutions of the first aspect, said L has a chemical structure of general Formula (Ⅴ) :
wherein, Y3 and Z3 are O, S or NH; W6 and W7 are absent, O, NH, C1-C6 linear alkyl, ori and n' independently are positive integers of 0-16; M3 and M4 of the spiro cyclic moiety independently are selected from the group consisting of NH or CH; j, k, l, and m' independently are selected from the group consisting of 0, 1, 2, 3; Q8 and Q9 independently are -CH2-, NH, or O.
In any of the above-metioned technical solutions of the first aspect, said L has any of the following structures:
In any of the above-metioned technical solutions of the first aspect, said C1-C6 linear alkyl is selected from the group consisting of any of the following groups:
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein z, at each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein the left-most O is optionally replaced by NH.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein the right-most O is optionally replaced by NH.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein one or more (e.g., 1, 2, 3, or 4) O of (O (CH2) y) z is optionally replaced by NH.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) x are optionally substituted with oxo (=O) .
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) y are optionally substituted with oxo (=O) .
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z-O-, wherein one CH2 of - (CH2) x-is optionally replaced by a piperazin-1, 4-diyl or a 7-to 11-membered saturated diazaspirocyclo-diyl (e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl) .
In any of the above-metioned technical solutions of the first aspect, said L is attached to the tropomyosin-related kinase ligand via the - (piperidin-1, 4-diyl) -O-comprised in L, wherein the piperidin-1, 4-diyl is attached to the left part at its position 1 and is attached to the right part at its position 4.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein z, at each occurrence, is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein the left-most O is optionally replaced by NH.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein the right-most O is optionally replaced by NH.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein one or more (e.g., 1, 2, 3, or 4) O of (O (CH2) y) z is optionally replaced by NH.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein the piperidin-1, 4-diyl is attached to the left part at its position 1 and is attached to the right part at its position 4.
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) x are optionally substituted with oxo (=O) .
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) y are optionally substituted with oxo (=O) .
In any of the above-metioned technical solutions of the first aspect, said L is -O- (CH2) x- (O (CH2) y) z- (piperidin-1, 4-diyl) -O-, wherein one CH2 of - (CH2) x-is optionally replaced by a piperazin-1, 4-diyl or a 7-to 11-membered saturated diazaspirocyclo-diyl (e.g., 2, 6-diazaspiro [3.3] heptan-2, 6-diyl or 3, 9-diazaspiro [5.5] undecan-3, 9-diyl) .
In any of the above-metioned technical solutions of the first aspect, said L is (piperidin-1, 4-diyl) - (CH2) x- (piperidin-1, 4-diyl) - (CH2) y- (piperidin-1, 4-diyl) -O-.
In any of the above-metioned technical solutions of the first aspect, said L is (piperidin-1, 4-diyl) - (CH2) x- (piperidin-1, 4-diyl) - (CH2) y- (piperidin-1, 4-diyl) -O-, wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is (piperidin-1, 4-diyl) - (CH2) x- (piperidin-1, 4-diyl) - (CH2) y- (piperidin-1, 4-diyl) -O-, wherein y, at each occurrence, is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
In any of the above-metioned technical solutions of the first aspect, said L is (piperidin-1, 4-diyl) - (CH2) x- (piperidin-1, 4-diyl) - (CH2) y- (piperidin-1, 4-diyl) -O-, wherein each of the piperidin-1, 4-diyls is attached to the left part at its position 1 and is attached to the right part at its position 4.
In any of the above-metioned technical solutions of the first aspect, said L is (piperidin-1, 4-diyl) - (CH2) x- (piperidin-1, 4-diyl) - (CH2) y- (piperidin-1, 4-diyl) -O-, wherein one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) x are optionally substituted with oxo (=O) .
In any of the above-metioned technical solutions of the first aspect, said L is (piperidin-1, 4-diyl) - (CH2) x- (piperidin-1, 4-diyl) - (CH2) y- (piperidin-1, 4-diyl) -O-, wherein one or more (e.g., 1, 2, 3, or 4) CH2 of (CH2) y are optionally substituted with oxo (=O) .
In any of the above-metioned technical solutions of the first aspect, said L is
In any of the above-metioned technical solutions of the first aspect, said L is
In any of the above-metioned technical solutions of the first aspect, as E3 ubiquitin ligase ligand, VH032, Lenalidomide, Pomalidomide, and Thalidomide have the following structures, respectively.
In any of the above-metioned technical solutions of the first aspect, VH032 is attached to L via a bond formed after removing the acetyl in its structure.
In any of the above-metioned technical solutions of the first aspect, Lenalidomide and Pomalidomide are attached to L via a bond formed after removing the NH2 in their structures.
In any of the above-metioned technical solutions of the first aspect, Thalidomide is attached to L via a bond formed after removing the H at position 4 or 5 of its 1, 3-dioxoisoindoline.
In one technical solution of the first aspect, any of the following compounds is included:
In one technical solution of the first aspect, said compound is the title compound of any of Examples 1-38.
In one technical solution of the first aspect, said compound is the title compound of any of Examples 5, 9, 11, 12, 25, 26, and 33.
In any of the above-metioned technical solutions of the first aspect, said compound further includes: a pharmaceutically acceptable salt, stereisomer, ester, prodrug, solvate and deuterated compound of said compound.
In any of the above-metioned technical solutions of the first aspect, said compound is a protein kinase degrading agent. Preferably, said protein kinase is TRK. Preferably, said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
In the second aspect, the present invention further provides a pharmaceutical composition comprising the above-mentioned compound. Preferably, said protein kinase is TRK. Preferably, said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
In the third aspect, the present invention further provides use of the above-mentioned compound useful as a protein kinase degrading agent or the above-mentioned pharmaceutical composition in the manufacture of a medicament for the prevention, diagonosis or treatment of protein kinase mediated diseases caused by the expression, mutation or fusion of a protein kinase. Preferably, said protein kinase is TRK. Preferably, said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
Preferably, said protein kinase mediated disease is tumor including at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
Preferably, the administration route of said medicament includes at least one of oral, intracutaneous injection, subcutaneous injection, application onto skin, parenteral, and rectal administration.
In the fourth aspect, the present invention further provides a method for the prevention, diagonosis or treatment of protein kinase mediated diseases caused by the expression, mutation or fusion of a protein kinase, said method comprising administering the above-mentioned compound useful as a protein kinase degrading agent to a subject in need thereof. Preferably, said protein kinase is TRK. Preferably, said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
Preferably, said protein kinase mediated disease is tumor including at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
In the fifth aspect, the present invention further provides the above-mentioned compound useful as a protein kinase degrading agent, for use of the prevention, diagonosis or treatment of
protein kinase mediated diseases caused by the expression, mutation or fusion of a protein kinase. Preferably, said protein kinase is TRK. Preferably, said TRK is wild-type TRK, fused TRK, mutant TRK or fused mutant TRK.
Preferably, said protein kinase mediated disease is tumor including at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
As used herein, the term “alkyl” refers to saturated or unsaturated, linear, branched or cyclic alkyl carbon chain with up to 10 carbon atoms. The linear alkyl includes, e.g., methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. The branched alkyl includes, e.g., isopropyl, sec-butyl, isobutyl, tert-butyl, neo-pentyl. The cycloalkyl includes, e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The unsaturated alkyl includes, e.g., alkyl carbon chain containing double bond, conjugated double bond, or triple bond. Alkyl may be substituted by one or more substituents, the non-limiting examples of the substituents include NH2, NO2, N (CH3) 2, ONO2, F, Cl, Br, I, OH, OCH3, CO2H, CO2CH3, CN, nitronyl, aryl and heteroaryl. The term “alkyl” also refers to unsubstituted or substituted linear, branched or cyclic alkyl containing a chain of up to 10 carbon atoms with at least one heteroatom (for instance, nitrogen, oxygen or sulfur) . The above-mentioned linear alkyl includes, for instance, CH2CH2OCH3, CH2CH2N (CH3) 2 and CH 2CH2SCH3. The branched groups include, for instance, CH2CH (OCH3) CH3, CH2CH (N (CH3) 2) CH3 and CH2CH (OCH3) CH3. The above-mentioned cyclic groups include, for instance, six-membered cyclic CH (CH2CH2) 2O, CH (CH2CH2) 2NCH3 and CH (CH2CH2) 2S and the corresponding five-member ring, and the like. The above-mentioned alkyl may be substituted by one or more substituents. The non-limiting examples of the above-mentioned substituents include NH2, NO2, N (CH3) 2, ONO2, F, Cl, Br, I, OH, OCH3, CO2H, CO2CH3, CN, aryl and heteroaryl. As used herein, the term “aryl” refers to substituted or unsubstituted aromatic compounds, carbocyclic groups and heteroaryl. Aryl is a monocyclic or is a polycyclic fused compound. For instance, phenyl is a monocyclic aryl. Naphthyl is an example with polycyclic fused aryl. Aryl may be substituted by one or more substituents, and the non-limiting examples of the substituents include NH2, NO2, N (CH3) 2, ONO2, F, Cl, Br, I, OH, OCH3, CO2H, CO2CH3, CN, nitronyl, aryl and heteroaryl. Heteroaryl is directed to substituted or unsubstituted monocyclic or polycyclic groups, ring members include at least one heteroatom, such as nitrogen, oxygen and sulfur. For examples, typical heterocyclyl includes one or more nitrogen atom, such as tetrazolyl, pyrrolyl, pyridinyl (e.g., 4-pyridinyl, 3-pyridinyl, 2-pyridinyl and the like) , pyridazinyl, indolyl, quinolinyl (such as 2-quinolinyl, 3-quinolinyl, etc. ) , imidazolyl, isoquinolinyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridonyl or pyridazinyl; Typical heterocyclyls containing one oxygen atom include 2-furanyl, 3-furanyl or benzofuranyl; Typical groups containing sulfur heteroatom include thienyl and benzothienyl; Typical groups containing mixed heteroatoms include furazanyl, oxazolyl, isooxazolyl, thiazolyl, and phenoxthinyl. Heterocyclic groups can be substituted by one or more substituents. These substituents include NH2, NO2, O-alkyl, NH-alkyl, N (alkyl) 2, NHC (O) -alkyl, ONO2, F, Cl, Br, I, OH, OCF3, OSO2CH3, CO2H, CO2-alkyl, CN, nitronyl, and aryl
and polyaryl. These situations also include the oxidation of heteroatoms within the ring, such as the formation of N-oxides, ketones, or sulfones.
The compound involved in the Examples of the present invention may be used a pharmaceutical active ingredient in a therapeutically effective amount for the preparation of a specific drug together with pharmaceutically acceptable carriers and excipients, for the prevention, diagonosis or treatment of a protein kinase mediated disease caused by the expression, mutation or fusion of a protein kinase. Said disease is preferably tumor, tumor includes at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast. Wherein, the therapeutically effective amount refers to the dosage needed to achieve the therapeutical effect.
As used herein, the term “pharmaceutically acceptable” refers to the absence of unacceptable toxicity in compounds such as salts or excipients. Pharmaceutically acceptable salts include inorganic anions, such as chloride ion, bromine ion, iodine ion, sulfate ion, sulfite ion, nitrate ion, nitrite ion, phosphate ion, hydrogen phosphate ion, and the like. Organic anions include acetate ion, propionate ion, cinnamate ion, benzenesulfonate ion, citrate ion, lactate ion, gluconate ion, and the like. The pharmaceutically acceptable excipients are described in the following text.
The compound of the Examples of the present invention can be made into various dosage forms, including solid dosage forms, semi-solid dosage forms, liquid dosage forms, and aerosols (Remington’s Pharmaceutical Sciences, Mack Publishing Company (1995) , Philade lphia, PA, 19th ed) . The specific dosage forms in these types of dosage forms include tablets, pills, lozenges, granules, gel, plasters, solutions, suppositories, injections, inhalants and sprays. These dosage forms can be used for both local or systemic administration as well as rapid or sustained release administration. There are many methods of administration for these drugs, including oral administration, buccal administration, rectal administration, peritoneal administration, intraperitoneal administration, superficial administration, subcutaneous administration, and tracheal administration, and the like.
The compound of the Examples of the present invention can be formulated into a solution, suspension, and emulsion using water-soluble or lipophilic solvents during injection administration. Lipophilic solvents specifically include vegetable oils and similar oils, synthetic fatty acid glycerides, higher aliphatic acid esters, and glycol esters (roylene glycol) , which are more readily soluble in Hank’s solution, Ringer’s solution, or physiological saturated NaCl aqueous solution.
When the compound in the Examples of the present invention is administered orally, it can be compounded with pharmaceutically acceptable excipients by common technical means in the art. These excipients can make these compounds into various dosage forms that can be used by patients, such as tablets, pills, suspensions, gel, and the like. There are various methods for preparing oral formulations, such as first mixing the compound and solid excipient, thoroughly grinding the mixture, adding appropriate excipients, and processing it into granules. The excipients that can be used to make oral dosage forms include: sugars such as lactose, sucrose, mannitol or sorbitol; Cellulose, such as corn starch, wheat starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxyproylmethyl-cellulose, methyl cellulose sodium, polyvinyl pyrrolidone, and the like.
The compound of the Examples of the present invention can also be made into a spray, which is realized through a pressurizer and a nebulizer or a dry powder inhalation device. Suitable injection agent that can be used in an injector includes, e.g., dichloro difluoromethane, fluorotrichloromethane, dichloro tetrafluoroethane, carbon dioxide and dimethyl ether. The dosage of aerosol administration can be adjusted through the valve of the injector.
The various dosage forms of the compound of the Examples of the present invention are related to the therapeutically effective amount of the compound involved. The therapeutically effective amount of such groups of compounds depends on the patient receiving treatment. When determining the appropriate dosage, the patients’ weight, condition, medication regimen, and the subjective judgment of the prescription physicians should be taken into account. The therapeutically effective amount of the compounds and the derivatives thereof with multiple mechanisms of action should be determined by competent and experienced prescription physicians.
The Examples of the present invention further include an additional treatment plan applied to patients with protein kinase mediated diseases, which includes surgical treatment and radiation therapy.
In order to enable the above-mentioned implementation details and operations of the present invention to be clearly understood by those skilled in the art, and to significantly demonstrate the progressive performance of compound, pharmaceutical composition comprising the same and use thereof of the Examples of the present invention, the following examples are provided to illustrate the implementation of the present invention.
Effect Example 1: Determination of the Inhibition Rate against NTRK fused Ba/F3 cells
1) The effect of the compounds of the present invention on the proliferation of Ba/F3 cells containing NTRK fusion was evaluated by using viability assay of luminescent cells in the same batch.
2) The proliferation of Ba/F3 cells was detected by using CellTier Glo (CTG) detection kit.
Ba/F3 cell lines (Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C) were incubated at 37℃ in an incubator under 5%CO2. Regularly subcultured, cells in the logarithmic growth phase were taken for planking. Cells were stained with trypan blue and viable cells were counted, with a required cell viability rate of over 90%. The cell concentration was adjusted to an appropriate concentration. 95 μL of the cell suspension was added to each well in the compound detection cell plate, culture solution without cell (containing 0.1%) was added to the Min control well and cultured for 24 hours. 5 μL of the 20 *compound working solution was taken to add to the cell culture plate. In the Max control, 5 μL of mixed liquid of DMSO-cell culture solution was added. The final concentration of DMSO was 0.1%. The culture plate was incubated in an incubator at 37 ℃ and under 5%CO2 for 72 hours. After 72 hours, the cell culture plate was removed and balanced to room temperature for 10 minutes. 50μL of CellTiter-Glo working solution was added to each well. The culture plate was vibrated on a track shaker for 2 minutes to induce cell lysis. The luminescence signal was detected on the SpectraMax Paradigm reader and the corresponding fluorescence value RLU for each well was then obtained. The inhibition rate data against cell proliferation was processed using the following formula:
Inhibition Rate (Inh%) =100- (RLUDrug-RLUMin) / (RLUMax-RLUMin) *100%.
Inhibition Rate (Inh%) =100- (RLUDrug-RLUMin) / (RLUMax-RLUMin) *100%.
The inhibition rates corresponding to different concentrations of compounds were calculated in Excel.
The inhibition rate of the compound against the proliferation of Ba/F3 cells containing NTRK fusion and fusion mutation is provided at the end of each of the corresponding Examples.
Effect Example 2: Detection of the degradation ability of the compounds on target proteins by Western blot
1) Ba/F3-LMNA-NTRK1-G667C cells were cultured to a coverage of 60-70%, added with corresponding concentrations of the compounds, and cultured for 24 hours; after centrifuging at 8000 rpm for 3 minutes, cells were collected and added 68μl of ice-bathed RIPA lysis solution. It was mixed and allowed to stand on ice for 30 minutes. Every 10 minutes, it was vortexed and reversed to fully lyse, and centrifuged and then placed on ice.
2) It was then quantified with protein standards, sampled and treated with electrophoresis. After electrophoresis, the gel was taken out, clipped with PVDF film soaked in methanol for 30 s, sponge and filter paper, inserted into the electrophoresis tank, and the electrophoresis transfer was conducted at constant voltage of 100 V for 1.5 h.
3) After the completion of the electrophoresis transfer, the PVDF film was placed in a 5%skimmed milk blocking solution for 1 hour, and slowly washed 3 times in TBST for 10 minutes each time. The washed PVDF film was then placed in a box containing the first antibody and incubated in a shaking bed at 4℃ for 10-16 hours. The PVDF film was then taken out and slowly washed in TBST for 3 times, then added the secondary antibody and incubated at room temperature for 1 hour. After completion, the PVDF film was removed and washed with TBST for three times. The color developing solutions were mixed, evenly added to the surface of the film, exposed and developed in the Tanon 5200 luminescent imager, and photos were taken to save the image.
TRK degradation rate of Ba/F3-LMNA-NTRK1-G667C cells treated with the compound is provided at the end of each of the corresponding examples.
The information about the abbreviations used in the following Examples is as follows:
Cbz: benzyloxycarbonyl;
DIEA: N, N-diisopropylethylamine;
DMF: N, N-dimethylformamide;
DMSO: dimethylsulfoxide;
ESI: electrospray ionization;
FA: formic acid;
HATU: 2- (7-azabenzotriazol) -N, N, N', N'-tetramethylurea hexafluorophosphate;
HPLC: High Performance Liquid Chromatography;
MS: Mass Spectrum;
NMP: N-methylpyrrolidinone;
NMR: nuclear magnetic resonance spectrum;
PE: petroleum ether;
Ph: phenyl;
TEA: triethylamine;
TFA: trifluoroacetic acid;
THF: tetrahydrofuran.
Example 1: 1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamido) butyl) carbamate
The title compound of Example 1 was synthesized according to the synthetic route as shown below.
Step 1: Methyl 2-methyl-3- ( (trimethylsilyl) ethynyl) benzoate (1-1)
Under an atmosphere of argon, to a 250mL round bottom flask were added methyl 3-iodo-2-methyl benzoate (15.0g, 54.3mmol) , CuI (2.06g, 10.8mmol) , THF (150mL) , TEA (27.4g, 271mmol) , ethynyl trimethylsilane (13.3g, 135mmol) , and (PPh3) 2PdCl2 (3.81g, 5.43mmol) , and the resulting mixutre was stirred at room temperature for 4 hr. Next, the reaction mixture was poured into iced water (500mL) . The aqueous phase was extracted with EtOAc (500mL*3) . The organic phase was combined and washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc (v/v) = 20: 1) to provide product 1-1 (12.0g, 48.7mmol, yield: 89.7%) , as colorless oil. 1HNMR (400MHz, CDCl3) : δ 7.79 (dd, J = 8.0, 1.6 Hz, 1H) , 7.59 (dd, J = 7.6 Hz, 1.2 Hz, 1H) , 7.17 (t, J = 7.6 Hz, 1H) , 3.89 (s, 3H) , 2.69 (s, 3H) , 0.27 (s, 9H) .
Step 2: Methyl 3-ethynyl-2-methylbenzoate (1-2)
To a 250mL round bottom flask were added methyl 2-methyl-3- ( (trimethylsilyl) ethynyl) benzoate (12.0g, 48.7mmol) , K2CO3 (13.4g, 97.4mmol) and MeOH (100mL) , the mxiture was stirred at room temperature for 16 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (PE: EtOAc (v/v) =10: 1) to provide the product 1-2 (7.00g, 40.2mmol, yield: 82.5%) , as colorless oil. 1HNMR (400MHz, CDCl3) : δ 7.82 (dd, J = 8.0 Hz, 1.2 Hz, 1H) , 7.62 (dd, J = 7.6 Hz, 1.2 Hz, 1H) , 7.20 (dd, J = 8.0 Hz, 1H) , 3.90 (s, 3H) , 3.32 (s, 1H) , 2.71 (s, 3H) .
Step 3: Methyl 3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzoate (1-3)
Under an atmosphere of argon, methyl 3-ethynyl-2-methylbenzoate (5.00g, 28.7mmol) , 6-chloro-3-iodoimidazo [1, 2-b] pyridazine (8.02g, 28.7mmol) , (PPh3) 2PdCl2 (2.01g, 2.87mmol) , CuI (5.48g, 28.7mmol) , and TEA (30mL) were dissolved in DMF (400mL) , and stirred at room temperature for 16 hr. After completion of the reaction, the reaction mixture was poured into H2O (1L) , and filtered. The resulting filter residue was washed with MeOH (200mL) to provide the product 1-3 (2.60g, 7.98mmol, yield: 27.8%) , as a yellow solid. MS (ESI) m/z: 326.0 [M+H] +.
Step 4: 3- ( (6-Chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzoic acid (1-4)
To a 100mL round bottom flask were added methyl 3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzoate (2.60g, 7.98mmol) , LiOH. H2O (1.68g, 39.9mmol) , THF (26mL) and H2O (26mL) . Then the resulting mixture was heated to 40℃ and stirred for 16 hr. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure to remove THF, and diluted with water (100mL) . The aqueous phase was extracted with DCM (100mL*3) to remove the impurities. The aqueous phase was acidified with diluted hydrochloric acid (1M) to pH=2, extracted with DCM (100mL*3) . The organic phase from the first and the second extraction was combined and washed with saturated NaCl aqueous solution (200mL) , dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was slurried with MeOH (20mL) and filtered to provide the product 1-4 (2.00g, 6.42mmol, yield: 80.4%) , as a yellow solid. MS (ESI) m/z: 312.1 [M+H] +.
Step 5: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (1-5)
3- ( (6-Chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzoic acid (2.00g, 6.42mmol) and 3-chloro-5- (trifluoromethyl) aniline (2.50g, 12.8mmol) were dispersed in pyridine (30mL) and cooled to 0℃. To the mixture was added dropwise POCl3 (1.97g, 12.8mmol) slowly. The resulting mixture was stirred for 20 min at the temperature maintained at 0℃. After completion of the reaction, the reaction mixture was poured into iced water (100mL) and stirred for 30 min. The aqueous phase was extracted with DCM (50mL*3) . The organic phase was washed with diluted hydrochloric acid (1M) and then saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, to provide a residue. The residue was slurried with MeOH (20mL) to provide the product 1-5 (1.80g, 3.68mmol, yield: 57.3%) , as a yellow solid. MS (ESI) m/z: 489.1 [M+H] +.
Step 6: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4-hydroxypiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (1-6)
N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (1.10g, 2.25mmol) , piperidin-4-ol (455mg, 4.50mmol) , and K2CO3 (932mg, 6.75mmol) were dispersed in DMF (10mL) , heated to 100℃, and stirred for 16 hr. After completion of the reaction, the reaction system was cooled to room temperature. The reaction mixure was poured into water (50 mL) and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) =30: 1) to provide the product 1-6 (700mg, 1.26mmol, yield: 56.0%) , as a yellow solid. MS (ESI) m/z: 554.1 [M+H] +.
Step 7: 1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4-nitrophenyl) carbonate (1-7)
N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4-hydroxypiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (300mg, 0.542mmol) , 4-dimethylaminopyridine (7mg, 0.0542mmol) , and pyridine (128mg, 1.63mmol) were dispersed in DCM (4mL) . To the mixture was slowly added 4-nitrophenyloxycarbonyl chloride (218mg, 1.08mmol) under stirring at room temperature. The resulting mixture was stirred at room temperature for 16 hr. Afther completion of the reaction, the reaction mixture was concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (100%EtOAc) to provide the product 1-7 (200mg, 0.278mmol, yield: 51.3%) , as a white solid. MS (ESI) m/z: 719.4 [M+H] +.
Step 8: tert-Butyl 2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxyacetate (1-8)
2- (2, 6-Dioxopiperidin-3-yl) -4-hydroxyisoindolin-1, 3-dione (1.00g, 3.64mmol) and tert-butyl 2-bromoacetate (710mg, 3.64mmol) were dissolved in DMF (10mL) , to which K2CO3 (1.00g, 7.25mmol) was added, and the resulting mixture was stirred at room temperature for 16 hr. After
completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) =1: 1) to provide the product 1-8 (450mg, 1.16mmol, yield: 31.8%) , as a white solid. MS (ESI) m/z: 333.0 [M+H-56] +.
Step 9: 2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetic acid (1-9)
tert-Butyl 2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxyacetate (450mg, 1.16mmol) was dissolved in DCM (1mL) , to which TFA (1mL) was added, and the resulting mixture was stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to provide the product 1-9 (350mg, 1.05mmol) , as a white solid, which was used directly for the next step. MS (ESI) m/z: 333.0 [M+H] +.
Step 10: tert-Butyl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamido) butyl) carbamate (1-10)
To a 25mL round bottom flask were added 2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetic acid (350mg, 1.05mmol) , tert-butyl (4-aminobutyl) carbamate (397mg, 2.11mmol) , HATU (600mg, 1.58mmol) , DIEA (492mg, 3.81mmol) and DMF (2mL) , and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was diluted with water (10mL) and extracted with EtOAc (20mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target compound 1-10 (350mg, 0.697mmol, yield: 66.4%) , as a white solid. MS (ESI) m/z: 403.2 [M+H-100] +.
Step 11: N- (4-Aminobutyl) -2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamide (1-11)
tert-Butyl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamido) butyl) carbamate (350mg, 0.697mmol) was dissolved in a mixture of TFA (1mL) and DCM (1mL) , and the resulting mixture was stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to provide the target compound 1-11 (350mg, TFA salt 1: 1) , as a white solid, which was used directly for the next step. MS (ESI) m/z: 403.2 [M+H] +.
Step 12: 1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamido) butyl) carbamate
1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4-nitrophenyl) carbonate (100mg, 0.139mmol) , N- (4-aminobutyl) -2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) acetamide (56mg, 0.139mmol) , and DIEA (54mg, 0.417mmol) were dispersed in NMP (1mL) , and the resulting mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was directly purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the product (28.7mg, 0.0292mmol, yield: 21.0%) , as a white solid. 1HNMR (400MHz, DMSO-d6) : δ 11.11 (s, 1H) , 10.91 (s, 1H) , 8.14–8.10 (m, 2H) , 7.97–7.90 (m, 3H) , 7.81 (d, J = 7.6Hz, 1H) , 7.69 (dd, J = 7.6 Hz, 0.8 Hz, 1H) , 7.59–7.58 (m, 1H) , 7.55 (dd, J = 8.0 Hz, 0.8 Hz, 1H) , 7.49 (d, J = 7.2 Hz, 1H) , 7.43–7.40 (m, 1H) , 7.39–7.32 (m, 2H) , 7.09 (t, J = 5.6 Hz, 1H) , 5.14–5.09 (m, 1H) , 4.80–4.70 (m, 3H) , 3.99–3.93 (m, 2H) , 3.43–3.41 (m, 2H) , 3.15–3.11 (m, 2H) , 2.98–2.93 (m, 2H) , 2.90–2.86 (m, 1H) , 2.63 (s, 3H) , 2.57–2.53 (m, 2H) , 2.05–2.01 (m, 1H) , 1.96–1.90 (m, 2H) , 1.64–1.53 (m, 2H) , 1.45–1.35 (m, 4H) . MS (ESI) m/z: 1004.6 [M+Na] +.
The inhibition rate of the title compound of Example 1 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was >90%.
Example 2: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The synthetic route is shown as follows:
Step 1: 6- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoic acid (2-1)
Under an atmosphere of argon, 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindolin-1, 3-dione (1.00g, 3.62mmol) , 6-aminohexanoic acid (594mg, 4.53mmol) and DIEA (1.41g, 10.9mmol) were dissolved in NMP (10mL) and the resulting mixture was heated to 140℃ and stirred for 2 hr. After completion of the reaction, the reaction system was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (30mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) =1: 1) to provide the product 2-1 (800mg, 2.07mmol, yield: 57.1%) , as green oil. MS (ESI) m/z: 388.2 [M+H] +.
Step 2: tert-Butyl 4- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-carboxylate (2-2)
N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (688mg, 1.41mmol) , tert-butyl 4- (piperidin-4-yloxy) piperidin-1-carboxylate (400mg, 1.41mmol) , K2CO3 (584mg, 4.23mmol) were dispersed in DMF (10mL) and the resulting mixture was heated to 100℃ and stirred 16 hrs. After completion of the reaction, the reaction system was cooled to room temperature. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) =30: 1) to provide the product 2-2 (350mg, 0.475mmol, yield: 33.7%) , as a yellow solid. MS (ESI) m/z: 737.4 [M+H] +.
Step 3: N- (3-Chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (2-3)
tert-Butyl 4- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-carboxylate (350mg, 0.475mmol) was dissolved in mixed TFA (1mL) and DCM (1mL) , and the resulting mixture was stirred at room temperature for 2 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to provide the product 2-3 (350mg, TFA salt 1: 1, 0.466mmol) , as a yellow oil, which was used directly for the next step. MS (ESI) m/z: 637.2 [M+H] +.
Step 4: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
To a 25 mL round bottom flask were added 6- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) hexanoic acid (70mg, 0.181mmol) , N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (138mg, 0.218mmol) , HATU (83mg, 0.218mmol) , DIEA (141mg, 1.09mmol) and DMF (2mL) . The resulting mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was poured into water (20mL) and the aqueous phase was extracted with EtOAc (20mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The crude product was purified by preparative HPLC (mobile phase: acetonitrile-water, 0.1%TFA) , and then washed with saturated sodium bicarbonate aqueous solution (30mL) to provide the product (25.0mg, 0.0234mmol, yield: 13.7%) , as a yellow solid. 1HNMR (400MHz, DMSO-d6) : δ 11.09 (s, 1H) , 10.92 (s, 1H) , 8.13–8.11 (m, 2H) , 7.93–7.89 (m, 2H) , 7.68 (d, J = 7.2Hz, 1H) , 7.59–7.55 (m, 3H) , 7.42 (t, J = 7.6Hz, 1H) , 7.32 (d, J = 10.0Hz, 1H) , 7.08 (d, J = 8.4Hz, 1H) , 7.01 (d, J = 7.2Hz, 1H) , 6.53 (brs, 1H) , 5.07–5.02 (m, 1H) , 3.97–3.93 (m, 2H) , 3.85–3.81 (m, 1H) , 3.72–3.61 (m, 3H) , 3.30–3.25 (m, 4H) , 3.17–3.12 (m, 1H) , 3.04–2.99 (m, 1H) , 2.92–2.83 (m, 1H) , 2.63 (s, 3H) , 2.62–2.50 (m, 2H) , 2.29–2.27 (m, 2H) , 2.03–2.00 (m, 1H) , 1.91–1.88 (m, 2H) , 1.79–1.70 (m, 2H) , 1.61–1.48 (m, 6H) , 1.38-1.31 (m, 4H) . MS (ESI) m/z: 1006.4 [M+H] +.
The inhibition rate of the title compound of Example 2 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was >90%.
Example 3: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -dioxoisoindolin-4-yl) amino) -3-oxopropoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The synthetic route is shown as follows:
Step 1: Preparation of Intermediate 3-1
At 0℃, to the mixture of 2- (2- (benzyloxy) ethoxy) ethan-1-ol (10.0g, 51.0mmol) , TEA (10.3g, 102mmol) and DCM (100mL) was added p-toluenesulfonyl chloride (11.7g, 61.1mmol) . After being stirred at 0℃ for 2 hr, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (100mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) =10: 1) to provide the target product 3-1 (13.0g, 37.1mmol, yield: 72.8%) , as colorless oil. MS (ESI) m/z: 351.2 [M+H] +.
Step 2: Preparation of Intermediate 3-2
Under an atmosphere of argon, a mixture of 2- (2- (benzyloxy) ethoxy) ethyl 4-methylbenzenesulfonate (13.0g, 37.1mmol) , lithium bromide (32.2g, 371mmol) and acetone (130mL) was heated to 65℃ and stirred for 4 hr. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) =5: 1) to provide the product 3-2 (8.10g, 31.3mmol, yield: 84.3%) , as colorless oil. MS (ESI) m/z: 281.0 [M+Na] +.
Step 3: Preparation of Intermediate 3-3
Under an atmosphere of argon and at 0℃, to a solution of benzyl 4-hydroxypiperidin-1-carboxylate (2.30g, 9.78mmol) in DMF (20mL) was added NaH (704mg, 60%w/w, 17.6mmol) . After being stirred at 0℃ for 30 min, to the mixture was added ( (2- (2-bromoethoxy) ethoxy) methyl) benzene (3.80g, 14.7mmol) , and the resulting mixture was warmed up to room temperature and stirred for 16 hr. Then, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) =5: 1) to provide the product 3-3 (1.32g, 3.19mmol, yield: 32.7%) , as a yellow oil. MS (ESI) m/z: 414.2 [M+H] +.
Step 4: Preparation of Intermediate 3-4
Under an atmosphere of hydrogen (15psi) , a mixture of benzyl 4- (2- (2- (benzyloxy) ethoxy) ethoxy) piperidin-1-carboxylate (1.32g, 3.19mmol) , Pd/C (300mg, 10%w/w) , HCl (2mL, 2N solution in dioxane) and MeOH (30mL) was heated to 65℃ and stirred for 4 hr. Then, the reaction mixture was filtered. The resulting filtrate was concentrated under reduced pressure to provide the target product 3-4 (650mg, crude) , as colorless oil, which was directly used in the next step. MS (ESI) m/z: 190.2 [M+H] +.
Step 5: Preparation of Intermediate 3-5
At 0℃, to a solution of 2- (2- (piperidin-4-yloxy) ethoxy) ethan-1-ol (650mg, crude) and TEA (1.04g, 10.3mmol) in DCM (8mL) was added CbzCl (878mg, 5.15mmol) . After being stirred at room temperature for 2 hr, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target product 3-5 (500mg, 1.55mmol, yield: 48.6%in two steps) , as a yellow oil. MS (ESI) m/z: 324.2 [M+H] +.
Step 6: Preparation of Intermediate 3-6
Under an atmosphere of argon, benzyl 4- (2- (2-hydroxyethoxy) ethoxy) piperidin-1-carboxylate (400mg, 1.24mmol) was dissolved in DMF (2mL) and the mixture was placed in iced water bath, to which NaH (99mg, 60%w/w, 2.47mmol) was added. After being stirred for 30 min, tert-butyl 3-bromopropionate (518mg, 2.48mmol) was added. The reaction mixture was naturally warmed up to room temperature and stirred for 16 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the product 3-6 (130mg, 0.329mmol, yield: 26.5%) , as a yellow oil. MS (ESI) m/z: 396.2 [M+H] +.
Step 7: Preparation of Intermediate 3-7
3- (2- (2- ( (1- ( (Benzyloxy) carbonyl) piperidin-4-yl) oxy) ethoxy) ethoxy) propanoic acid (130mg, 0.329mmol) was dissolved in MeOH (10mL) , to which Pd/C (35mg, 10%w/w) was added and the resulting mixture was stirred at room temperature under the atmosphere of hydrogen (15psi) for 2 hr. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure so as to provide the product 3-7 (80mg) , as a yellow oil, which was directly used in the next step. MS (ESI) m/z: 262.2 [M+H] +.
Step 8: Preparation of Intermediate 3-8
Under an atmosphere of argon, 3- (2- (2- (piperidin-4-yloxy) ethoxy) ethoxy) propanoic acid (80mg) , N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (150mg, 0.306mmol) , and K2CO3 (127mg, 0.918mmol) were dispersed in DMF (0.5mL) and the resulting mixture was heated to 100℃ and stirred for 16 hr. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with water (30mL) and the aqueous phase was extracted with EtOAc (30mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the product 3-8 (70mg, yield: 29.8%in two steps) , as a white solid. MS (ESI) m/z: 714.2 [M+H] +.
Step 9: Title compound of Example 3
3- (2- (2- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) ethoxy) ethoxy) propanoic acid (70mg, 0.098mmol) and 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (54mg, 0.196mmol) were dissolved in pyridine (2mL) and the mixture was cooled to 0℃, to which POCl3 (30mg, 0.196mmol) was added slowly. After completion of the addition, the resulting mixture was kept at that termperature and stirred for 20 min. After completion of the reaction, the reaction mixture was carefully quenched with MeOH (2mL) . The resulting solution was directly purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target final product (23.0mg, yield: 24.2%) , as a white solid. MS (ESI) m/z: 969.3 [M+H] +. 1HNMR (400MHz, DMSO-d6) : δ 11.13 (s, 1H) , 10.91 (s, 1H) , 9.84 (s, 1H) , 8.53 (d, J = 8.4Hz, 1H) , 8.20–8.08 (m, 2H) , 7.95–7.85 (m, 2H) , 7.82 (t, J = 7.6Hz, 1H) , 7.68 (d, J = 7.2Hz, 1H) , 7.62–7.52 (m, 3H) , 7.41 (t, J = 7.2Hz,
1H) , 7.30–7.27 (m, 1H) , 5.15–5.10 (m, 1H) , 3.95–3.85 (m, 2H) , 3.75–3.69 (m, 2H) , 3.60–3.42 (m, 11H) , 2.92–2.85 (m, 1H) , 2.70–2.65 (m, 2H) , 2.63 (s, 3H) , 2.62–2.56 (m, 2H) , 2.10–2.00 (m, 1H) , 1.94–1.82 (m, 2H) , 1.55-1.40 (m, 2H) .
The inhibition rate of the title compound of Example 3 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were >90%and >90%, respectively.
Example 4: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (3- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) propionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The synthetic route is shown as follows:
Step 1: Preparation of Intermediate 4-1
Under an atmosphere of argon, a mixture of 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindolin-1, 3-dione (1.00g, 3.62mmol) , tert-butyl 3- (2-aminoethoxy) propionate (856mg, 4.53mmol) , DIEA (1.40g, 10.9mmol) and NMP (10mL) was heated to 140℃ and stirred for 2 hr. After being cooled to room
temperature, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc=1: 1) to provide the target product 4-1 (1.40g, 3.14mmol, yield: 86.8%) , as green oil. MS (ESI) m/z: 468.3 [M+Na] +.
Step 2: Preparation of Intermediate 4-2
A solution of tert-butyl 3- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) propionate (1.40g, 3.14mmol) and TFA (5mL) in DCM (5mL) was stirred at room temperature for 2 hr. Then, the reaction mixture was concentrated under reduced pressure to provide the target product 4-2 (1.10g, 2.83mmol, yield: 90.1%) , as a yellow solid. MS (ESI) m/z: 390.2 [M+H] +.
Step 3: Preparation of the title compound of Example 4
A mixture of 2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) aminoethoxy) propanoic acid (70mg, 0.181mmol) , N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (138mg, 0.218mmol) , HATU (83mg, 0.218mmol) , DIEA (141mg, 1.09mmol) and DMF (2mL) was stirred at room temperature for 1 hr. Then, the reaction mixture was diluted with water (10mL) and extracted with EtOAc (20mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) , so as to provide the target final product (21.0mg, 0.0208mmol, yield: 11.5%) , as a yellow solid.
1HNMR (400MHz, DMSO-d6) : δ11.08 (s, 1H) , 10.92 (s, 1H) , 8.12 (s, 2H) , 7.93–7.89 (m, 2H) , 7.69 (d, J =7.6Hz, 1H) , 7.59–7.55 (m, 3H) , 7.44–7.40 (m, 1H) , 7.33–7.31 (m, 1H) , 7.12 (d, J =8.4Hz, 1H) , 7.02 (d, J =6.8Hz, 1H) , 6.58–6.55 (m, 1H) , 5.07–5.02 (m, 1H) , 3.98–3.92 (m, 2H) , 3.85–3.79
(m, 1H) , 3.72–3.58 (m, 8H) , 3.47–3.43 (m, 2H) , 3.18–3.11 (m, 1H) , 3.05–2.99 (m, 1H) , 2.91–2.83 (m, 1H) , 2.64 (s, 3H) , 2.63–2.51 (m, 5H) , 2.04–1.98 (m, 1H) , 1.92–1.83 (m, 2H) , 1.77–1.68 (m, 2H) , 1.51–1.43 (m, 2H) , 1.39–1.24 (m, 2H) . MS (ESI) m/z: 1008.1 [M+H] +.
The inhibition rate of the title compound of Example 4 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.6%and 99.7%, respectively. The TRK degradation rate of Ba/F3-LMNA-NTRK1-G667C cells after being treated with the title compound of Example 4 at a concentration of 0.10 μM was 60.16%.
Example 5: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amnio) ethoxy) ethoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Step 1: Preparation of Intermediate 5-1
At 0℃, to a solution of benzyl 4-hydroxypiperidin-1-carboxylate (275mg, 1.17mmol) in anhydrous DMF (3mL) was added NaH (94mg, 60%wt, 2.34mmol) . After being stirred at 0℃ for 30 min, tert-butyl (2- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) ethyl) carbamate (500mg, 1.40mmol) was added to the reaction mixture, which was continueously stirred overnight at room temperature. Then, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (20mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target compound 5-1 (150mg, 0.294mmol, yield: 25.1%) as a yellow oil. MS (ESI) m/z: 533.4 [M+Na] +.
Step 2: Preparation of Intermediate 5-2
Under an atmosphere of hydrogen (15psi) , a mixture of benzyl 4- ( (2, 2-dimethyl-4-oxo-3, 8, 11, 14-tetraoxa-5-azahexadecan-16-yl) oxy) piperidin-1-carboxylate (150mg, 0.294mmol) , Pd/C (20mg, 10%w/w) and MeOH (10mL) was stirred at room temperature for 4 hr. Then, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to provide the target compound 5-2 (100mg, crude) , as colorless oil, which was directly used in the next step. MS (ESI) m/z: 377.2 [M+H] +.
Step 3: Preparation of Intermediate 5-3
A mixture of N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (119mg, 0.244mmol) , tert-butyl (2- (2- (2- (2- (piperidin-4-yloxy) ethoxy) ethoxy) ethoxy) ethyl) carbamate (100mg, crude) , K2CO3 (101mg, 0.732mmol) and DMF (1mL) was heated to 100℃ and stirred overnight. After being cooled to room temperature, the reaction mixture was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target compound 5-3 (100mg, 0.121mmol, yield: 41.0%in two steps) , as a yellow oil. MS (ESI) m/z: 829.8 [M+H] +.
Step 4: Preparation of Intermediate 5-4
tert-Butyl (2- (2- (2- (2- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) ethoxy) ethoxy) ethoxy) ethyl) carbamate (100mg, 0.121mmol) and TFA (1mL) were dissolved in DCM (3mL) and the mixture was stirred at room temperature for 2 hr. Then, the reaction mixture was concentrated under reduced pressure to provide the target compound 5-4 (100mg, TFA salt 1: 1, 0.119mmol, yield: 98.3%) , as a yellow oil. MS (ESI) m/z: 729.3 [M+H] +.
Step 5: Preparation of the title comound of Example 5
Under an atmosphere of argon, 3- ( (6- (4- (2- (2- (2-aminoethoxy) ethoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide (100mg, 0.119mmol) , 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindolin-1, 3-dione (66mg, 0.238mmol) and DIEA (62mg,
0.476mmol) were dissolved in NMP (1mL) and the mixture was heated to 140℃ and stirred for 2 hr. Then, the reaction mixture was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target final product (25.9mg, 0.0263mmol, yield: 22.1%) , as a yellow solid.
1HNMR (400MHz, DMSO-d6) : δ 11.08 (s, 1H) , 10.93 (s, 1H) , 8.13 (s, 2H) , 7.91–7.88 (m, 2H) , 7.68 (d, J = 7.6Hz, 1H) , 7.59–7.52 (m, 3H) , 7.42 (t, J = 7.6Hz, 1H) , 7.34 (d, J = 10.0 Hz, 1H) , 7.09 (d, J = 8.4Hz, 1H) , 7.00 (d, J = 7.2Hz, 1H) , 6.57 (t, J = 4.8Hz, 1H) , 5.06–5.02 (m, 1H) , 3.97–3.90 (m, 2H) , 3.63–3.46 (m, 17H) , 3.27–3.25 (m, 2H) , 2.92–2.83 (m, 1H) , 2.64 (s, 3H) , 2.59–2.55 (m, 2H) , 2.07–1.99 (m, 1H) , 1.95–1.85 (m, 2H) , 1.55–1.45 (m, 2H) . MS (ESI) m/z: 985.5 [M+H] +.
The inhibition rate of the title compound of Example 5 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were >90%and >90%, respectively. The TRK degradation rate of Ba/F3-LMNA-NTRK1-G667C cells after being treated with the title compound of Example 5 at a concentration of 0.10 μM was 86.08%.
Example 6: 1- (3- (3- (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4- (2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) acetamido) butyl) carbamate
The synthetic route is shown as follows:
Step 1: Preparation of Intermediate 6-1
Under an atmosphere of argon, tert-butyl glycinate (800mg, 6.10mmol) , 2- (2, 6-dioxopiperidin-3-yl) -4-fluoroisoindolin-1, 3-dione (1.12g, 4.07mmol) and DIEA (1.57g, 12.2mmol) were dissolved in NMP (12mL) , and then the mixture was heated to 140℃ and stirred for 2 hr. After completion of the reaction, the reaction system was cooled to room temperature, diluted with water (50 mL) and extracted with EtOAc (30mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) =1: 1) to provide the target compound 6-1 (1.20g, 3.10mmol, yield: 76.2%) , as a yellow solid. MS (ESI) m/z: 332.1 [M+H-56] +.
Step 2: Preparation of Intermediate 6-2
tert-Butyl 2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycinate (1.20g, 3.10mmol) and TFA (3mL) were dissolved in DCM (10mL) and the mixture was stirred at room temperature for 3 hr. Then, the reaction mixture was concentrated under reduced pressure to provide the target compound 6-2 (850mg, 2.57mmol, yield: 82.9%) , as a yellow solid. MS (ESI) m/z: 332.0 [M+H] +.
Step 3: Preparation of Intermediate 6-3
(2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) glycine (850mg, 2.57mmol) , tert-butyl (4-aminobutyl) carbamate (380mg, 3.08mmol) , HATU (1.17g, 3.08mmol) and DIEA (994mg, 7.71mmol) were dissolved in DMF (10mL) and the mixture was stirred at room temperature for 2 hr. Then, the reaction mixture was diluted with water (50mL) and extracted with EtOAc (50mL*3) . The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to provide a residue. The residue was purified by silica gel column chromatography (PE: EtOAc=1: 1) to provide the target compound 6-3 (550mg, 1.10mmol, yield: 42.7%) , as a yellow solid. MS (ESI) m/z: 524.2 [M+Na] +.
Step 4: Preparation of Intermediate 6-4
tert-Butyl (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) acetamido) butyl) carbamate (550mg, 1.10mmol) and TFA (1mL) were dissolved in DCM (3mL) and the mixture was stirred at room temperature for 2 hr. Then, the reaction mixture was concentrated under reduced pressure to provide the target compound 6-4 (300mg, TFA salt 1: 1, 0.583mmol, yield: 58.2%) , as a yellow solid. MS (ESI) m/z: 402.0 [M+H] +.
Step 5: Preparation of the title comound of Example 6
1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl (4-nitrophenyl) carbonate (100mg, 0.139mmol) , N- (4-aminobutyl) -2- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) acetamide (56mg, 0.139mmol) and DIEA (54mg, 0.417mmol) were dissolved in NMP (1mL) and the mixture was stirred at room temperature for 1 hr. The reaction mixture was purified with preparative HPLC (mobile phase: acetonitrile-water, 0.1%FA) to provide the target final product (26.0mg, 0.0265mmol, yield: 19.1%) , as a yellow solid.
1HNMR (400MHz, DMSO-d6) : δ 11.10 (s, 1H) , 10.91 (s, 1H) , 8.12 (brs, 2H) , 8.09–8.06 (m, 1H) , 7.94–7.90 (m, 2H) , 7.68 (d, J =7.6Hz, 1H) , 7.60–7.54 (m, 3H) , 7.42 (t, J =7.6Hz, 1H) , 7.34–7.31 (m, 1H) , 7.10–7.05 (m, 2H) , 6.95–6.92 (m, 1H) , 6.84 (d, J =8.8Hz, 1H) , 5.09–5.04 (m, 1H) , 4.79–4.73 (m, 1H) , 3.98–3.87 (m, 4H) , 3.40–3.35 (m, 2H) , 3.10–3.07 (m, 2H) , 2.97–2.94 (m, 2H) ,
2.89–2.83 (m, 1H) , 2.63 (s, 3H) , 2.57–2.53 (m, 2H) , 2.04–2.00 (m, 1H) , 1.99–1.93 (m, 2H) , 1.65–1.55 (m, 2H) , 1.40–1.34 (m, 4H) . MS (ESI) m/z: 981.3 [M+H] +.
The inhibition rate of the title compound of Example 6 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was >90%.
Example 7: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Step 1: tert-Butyl (3- (4- ( (1- (3- ( (3- (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -3-oxopropyl) carbamate
At room temperature, to a 25 mL reaction flask were added N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (200 mg, 0.31 mmol) , DMF (4 mL) , 3- ( (tert-butyloxycarbonyl) amino) propanoic acid (89 mg, 0.47 mmol) and HATU (239 mg, 0.63 mmol) . The mixture was stirred at room temperature for 10 min, and then Et3N (95 mg, 0.94 mmol) was added. The resulting mixture was reacted at room temperature for 0.5 hr. After completion of the reaction, the reaction mixture was poured into water (100 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product 4-1 (190mg, yield: 74.8%) , as a yellow solid. MS (ESI) m/z: 708.2 [M+H-100] +.
Step 2: 3- ( (6- (4- ( (1- (3-Aminopropionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
At room temperature, to a 50 mL reaction flask were added tert-butyl (3- (4- ( (1- (3- ( (3- (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -3-oxopropyl) carbamate (190 mg, 0.24 mmol) , dichloromethane (3 mL) and TFA (2 mL) , and the mixture was stirred at room temperature for 2 hr. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent. To the residue was added water (30 mL) , and the resulting mixture was adjusted to pH=9-10 with 10%NaOH aqueous solution. The aqueous phase was extracted with EtOAc (30mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure, to provide 150 mg of product as a yellow solid, which was directly used in the next step. MS (ESI) m/z: 708.2 [M + H] +.
Step 3: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (3- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Under an atmosphere of nitrogen, to a 50 mL reaction flask were added 3- ( (6- (4- ( (1- (3-aminopropionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide (150 mg, 0.21 mmol) , NMP (3 mL) , 2- (2, 6-oxopiperidin-3-yl) -4-fluoroisoindolin-1, 3-dione (88 mg, 0.32 mmol) and Et3N (64 mg, 0.64 mmol) , and the mixture was heated to 90℃ and reacted for 3 hr. After completion of the reaction, the reaction mixture was poured into water (100 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product (70 mg, yield 34.3%) as a yellow solid. MS (ESI) m/z: 964.2 [M +H] +. 1H NMR (500 MHz, CDCl3) δ 8.51 –8.48 (m, 1H) , 8.28 –8.25 (m, 1H) , 8.05 (s, 1H) , 7.86 (s, 1H) , 7.73 (s, 1H) , 7.65 –7.61 (m, 2H) , 7.48 (t, J = 7.8 Hz, 1H) , 7.41 –7.38 (m, 2H) , 7.23 (d, J = 7.6 Hz, 1H) , 7.06 (d, J = 7.1 Hz, 1H) , 6.93 (d, J = 8.5 Hz, 1H) , 6.89 –6.82 (m, 1H) , 6.52 (t, J = 6.0 Hz, 1H) , 4.89 –4.85 (m,
1H) , 3.84 –3.76 (m, 3H) , 3.73 –3.53 (m, 5H) , 3.44 –3.19 (m, 4H) , 2.90 –2.52 (m, 8H) , 2.11 –2.07 (m, 1H) , 1.87 –1.82 (m, 2H) , 1.79 –1.46 (m, 4H) , 1.27 –1.22 (m, 2H) .
The inhibition rate of the title compound of Example 7 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 98.7%and 99.5%, respectively.
Example 8: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (4- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) butyryl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 7. MS (ESI) m/z: 978.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.32 (s, 1H) , 8.16 (s, 1H) , 8.04 (s, 1H) , 7.84 (s, 1H) , 7.76 (s, 1H) , 7.65 –7.61 (m, 2H) , 7.47 (t, J = 7.8 Hz, 1H) , 7.41 –7.38 (m, 2H) , 7.23 (d, J = 7.6 Hz, 1H) , 7.06 (d, J = 7.1 Hz, 1H) , 6.96 (d, J = 8.6 Hz, 1H) , 6.87 (d, J = 9.9 Hz, 1H) , 6.29 (t, J = 6.0 Hz, 1H) , 4.89 –4.85 (m, 1H) , 3.84 –3.76 (m, 3H) , 3.68 –3.65 (m, 3H) , 3.37 –3.20 (m, 6H) , 2.90 –2.68 (m, 6H) , 2.45 –2.41 (m, 2H) , 2.14 –2.08 (m, 1H) , 1.96 –1.82 (m, 4H) , 1.79 –1.46 (m, 4H) , 1.27 –1.22 (m, 2H) .
The inhibition rate of the title compound of Example 8 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.5%and 99.8%, respectively.
Example 9: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (3- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) propionyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 7. MS (ESI) m/z: 1096.4 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.65 (s, 1H) , 8.33 (s, 1H) , 8.04 (s, 1H) , 7.84 (s, 1H) , 7.77 (s, 1H) , 7.65 –7.61 (m, 2H) , 7.47 (t, J = 7.8 Hz, 1H) , 7.43 –7.36 (m, 2H) , 7.23 (d, J = 7.6 Hz, 1H) , 7.07 (d, J = 7.1 Hz, 1H) , 6.96 –6.86 (m, 2H) , 6.45 (t, J = 6.0 Hz, 1H) , 4.89 –4.85 (m, 1H) , 3.86 –
3.84 (m, 3H) , 3.78 –3.70 (m, 2H) , 3.69 –3.59 (m, 13H) , 3.47 –3.40 (m, 2H) , 3.38 –3.20 (m, 4H) , 2.87 –2.70 (m, 6H) , 2.61 –2.57 (m, 2H) , 2.13 –2.05 (m, 1H) , 1.96 –1.52 (m, 6H) , 1.35 –1.26 (m, 2H) .
The inhibition rate of the title compound of Example 9 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.9%and 99.8%, respectively.
Example 10: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) butyryl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 2. MS (ESI) m/z: 1022.4 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.20 (s, 1H) , 8.04 (s, 1H) , 7.88 –7.73 (m, 2H) , 7.65 –7.61 (m, 2H) , 7.47 –7.36 (m, 3H) , 7.28 –7.21 (m, 1H) , 7.16 –7.08 (m, 1H) , 6.95 –6.79 (m, 2H) , 4.97 –4.86 (m, 1H) , 4.11 –3.95 (m, 2H) , 3.94 –3.77 (m, 3H) , 3.75 –3.60 (m, 3H) , 3.59 –3.41 (m, 4H) , 3.41 –3.18 (m, 4H) , 2.99 –2.86 (m, 1H) , 2.81 –2.68 (m, 4H) , 2.44 –2.30 (m, 2H) , 2.15 –1.64 (m, 8H) , 1.42 –1.17 (m, 4H) .
The inhibition rate of the title compound of Example 10 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 88.3%and 99.1%, respectively.
Example 11: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (1- ( (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) piperidin-4-yl) methyl) piperidin-4-carbonyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 7. MS (ESI) m/z: 1101.3 [M+H] +. 1H NMR (500 MHz, DMSO-d6) δ 11.06 (s, 1H) , 10.90 (s, 1H) , 8.19 –8.08 (m, 2H) , 7.96 –7.86 (m, 2H) , 7.74 –7.64 (d, 2H) , 7.59 (s, 1H) , 7.56 (d, J = 7.4 Hz, 1H) , 7.42 (t, J = 7.6 Hz, 1H) ,
7.38 –7.26 (m, 3H) , 5.12 –5.04 (m, 1H) , 4.00 –3.91 (m, 2H) , 3.90 –3.82 (m, 1H) , 3.80 –3.62 (m, 5H) , 3.60 –3.50 (m, 2H) , 3.15 –2.78 (m, 9H) , 2.67 –2.56 (m, 5H) , 2.21 –2.00 (m, 3H) , 1.96 –1.22 (m, 18H) .
The inhibition rate of the title compound of Example 11 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.2%and 99.1%, respectively.
Example 12: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (2- (6- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) -2, 6-diazaspiro [3.3] heptan-2-yl) acetyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 7. MS (ESI) m/z: 1031.4 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.22 (s, 1H) , 8.13 –7.97 (m, 2H) , 7.88 –7.73 (m, 2H) , 7.70 –7.62 (m, 2H) , 7.46 –7.38 (m, 3H) , 7.31 –7.26 (m, 1H) , 7.15 (d, J = 7.0 Hz, 1H) , 6.88 (d, J = 9.9 Hz, 1H) , 6.55 (d, J = 8.5 Hz, 1H) , 4.95 –4.81 (m, 1H) , 4.31 (s, 4H) , 3.95 –3.78 (m, 3H) , 3.75 –3.61 (m, 3H) , 3.49 (s, 4H) , 3.41 –3.18 (m, 6H) , 2.91 –2.62 (m, 6H) , 2.14 –2.02 (m, 1H) , 1.99 –1.88 (m, 2H) , 1.87 –1.75 (m, 2H) , 1.74 –1.65 (m, 2H) , 1.55 –1.50 (m, 2H) .
The inhibition rate of the title compound of Example 12 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.7%and 99.1%, respectively.
Example 13: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (2- (1- (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) piperidin-4-yl) acetyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 7, MS (ESI) m/z: 1018.4 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.34 (s, 1H) , 8.13 –8.01 (m, 2H) , 7.84 (s, 1H) , 7.80 –7.74 (m, 2H) , 7.62 (d, J = 7.6 Hz, 1H) , 7.55 (t, J = 7.8 Hz, 1H) , 7.46 –7.39 (m, 2H) , 7.35 (d, J = 7.1 Hz, 1H) , 7.28 (s, 1H) , 7.15 (d, J = 8.4 Hz, 1H) , 6.93 (d, J = 9.9 Hz, 1H) , 4.98 –4.90 (m, 1H) , 3.95 –3.78
(m, 3H) , 3.76 –3.65 (m, 5H) , 3.48 –3.25 (m, 4H) , 2.94 –2.79 (m, 4H) , 2.70 (s, 3H) , 2.32 –2.25 (m, 2H) , 2.20 –2.05 (m, 3H) , 1.95 –1.78 (m, 6H) , 1.74 –1.65 (m, 2H) , 1.64 –1.46 (m, 4H) .
The inhibition rate of the title compound of Example 13 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 97.2%.
Example 14: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Step 1: tert-Butyl (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) carbamate (14-1)
N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (3.0 g, 6.13 mmol) , tert-butyl piperidin-4-ylcarbamate (1.8 g, 9.2 mmol) , and K2CO3 (1.7 g, 12.3 mmol) were dispersed in DMF (50mL) . The resulting mixture was heated to 110℃, stirred and reacted for 16 hr. After completion of the reaction, the reaction system was cooled to room temperature. The reaction mixture was poured into water (50 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) = 1: 1) to provide the product 14-1 (3.1 g, yield: 77.4%) as a white solid. MS (ESI) m/z: 653.2 [M+H] +.
Step 2: 3- ( (6- (4-Aminopiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
In a 50 mL reaction flask, tert-butyl (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) carbamate (2.5 g, 3.82 mmol)
was dissolved in DCM (10.0 mL) , and then TFA (10.0 mL) was added. The mixture was stirred at room temperature and reacted for 3 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and adjusted to pH = 7 with 5%NaHCO3 aqueous solution. The aqueous phase was extracted with EtOAc (150mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure, to provide 1.7 g of the target compound as a white solid, which was directly used in the next step. MS (ESI) m/z: 553.1 [M+H] +.
Step 3: tert-Butyl 4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyrate
Under an atmosphere of nitrogen, to a 50 mL reaction flask were added tert-butyl 4- (2-bromoethoxy) butyrate (250 mg, 0.94 mmol) , DMF (4 mL) , 5-amino-2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (332 mg, 1.22 mmol) and K2CO3 (388 mg, 2.81 mmol) . The mixture was stirred at room temperature and reacted for 3 hr. After completion of the reaction, the reaction mixture was poured into water (80 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) = 1: 1) to provide the product 14-3 (110 mg, yield: 25.6%) as a white solid. MS (ESI) m/z: 482.2 [M+Na] +.
Step 4: 4- (2- ( (2- (2, 6-Dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyric acid
In a 50 mL reaction flask, tert-butyl 4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyrate (110 mg, 0.24 mmol) was dissolved in DCM (3 mL) , and then TFA (2 mL) was added. The mixture was stirred at room temperature and reacted for 2 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give 100 mg of oil, which was directly used in the next step. MS (ESI) m/z: 404.1 [M+H] +.
Step 5: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
To a 50 mL round-bottom flask were added 3- ( (6- (4-aminopiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide (137 mg, 0.25 mmol) , DMF (4 mL) , 4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) butyric acid (100 mg, 0.25 mmol) , Et3N (100 mg, 0.99 mmol) and HATU (188 mg, 0.50 mmol) . The mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was poured into water (100 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (40 mg, yield: 17.2%) as a white solid. MS (ESI) m/z: 938.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.66 (s, 1H) , 8.07 (s, 1H) , 7.87 (s, 1H) , 7.75 (s, 1H) , 7.65 –7.52 (m, 2H) , 7.51 –7.34 (m, 3H) , 7.26 –7.22 (m, 1H) , 6.89 (s, 1H) , 6.82 –6.77 (m, 1H) , 6.71 –6.59 (m, 1H) , 6.48 –6.28 (m, 1H) , 4.90 –4.75 (m, 1H) , 4.53 (s, 2H) , 4.21 –3.84 (m, 5H) , 3.61 –3.30 (m, 4H) , 3.16 –2.99 (m, 2H) , 2.72 –2.58 (m, 5H) , 2.27 –2.10 (m, 2H) , 1.96 –1.74 (m, 4H) , 1.53 –1.40 (m, 2H) .
The inhibition rate of the title compound of Example 14 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 98.7%and 99.0%, respectively.
Example 15: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 14. MS (ESI) m/z: 982.0 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.77 (s, 1H) , 8.07 (s, 1H) , 7.88 (s, 1H) , 7.75 (s, 1H) , 7.62 –7.56 (m, 2H) , 7.52 –7.47 (m, 1H) , 7.43 –7.36 (m, 2H) , 7.26 –7.22 (m, 1H) , 6.92 (d, J = 2.1 Hz, 1H) , 6.82 –6.73 (m, 2H) , 6.42 (d, J = 7.9 Hz, 1H) , 4.85 –4.78 (m, 1H) , 4.53 (s, 2H) , 4.14 –3.81 (m, 5H) , 3.59 –3.37 (m, 8H) , 3.08 –2.99 (m, 2H) , 2.70 –2.63 (m, 5H) , 2.27 –2.21 (m, 2H) , 1.88 –1.82 (m, 4H) , 1.49 –1.41 (m, 2H) .
The inhibition rate of the title compound of Example 15 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 98.9%.
Example 16: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (5- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) amino) ethoxy) ethoxy) pentanamido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 14. MS (ESI) m/z: 996.4 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.56 (s, 1H) , 8.06 (s, 1H) , 7.85 (s, 1H) , 7.77 (s, 1H) , 7.67 –7.58 (m, 2H) , 7.52 (d, J = 8.2 Hz, 1H) , 7.46 –7.34 (m, 2H) , 7.31 –7.26 (m, 1H) , 6.93 (d, J = 2.1 Hz, 1H) , 6.87 –6.71 (m, 2H) , 6.20 (d, J = 7.9 Hz, 1H) , 4.89 –4.76 (m, 1H) , 4.51 (s, 2H) , 4.18 –3.80 (m, 5H) , 3.55 –3.41 (m, 8H) , 3.16 –2.99 (m, 2H) , 2.74 –2.61 (m, 5H) , 2.21 –2.13 (m, 2H) , 2.08 –1.85 (m, 3H) , 1.74 –1.63 (m, 3H) , 1.51 –1.36 (m, 2H) .
The inhibition rate of the title compound of Example 16 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 71.9%and 98.8%, respectively.
Example 17: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 14. MS (ESI) m/z: 939.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.54 (s, 1H) , 8.45 (s, 1H) , 8.04 (s, 1H) , 7.84 (s, 1H) , 7.73 (s, 1H) , 7.69 –7.54 (m, 3H) , 7.41 –7.36 (m, 3H) , 7.25 –7.20 (m, 1H) , 7.15 (dd, J = 8.3, 2.3 Hz, 1H) , 6.80 (d, J = 9.9 Hz, 1H) , 5.83 (d, J = 7.8 Hz, 1H) , 4.90 –4.83 (m, 1H) , 4.24 –4.20 (m, 2H) , 4.16 –4.04 (m, 2H) , 4.00 –3.87 (m, 1H) , 3.82 –3.78 (m, 2H) , 3.55 (t, J = 5.9 Hz, 2H) , 3.09 –3.00 (m, 2H) , 2.89 –2.61 (m, 6H) , 2.26 (t, J = 7.2 Hz, 2H) , 2.13 –2.07 (m, 1H) , 2.00 –1.88 (m, 4H) , 1.50 –1.40 (m, 2H) .
The inhibition rate of the title compound of Example 17 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 94.6%and 98.9%, respectively.
Example 18: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) ethoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 14. MS (ESI) m/z: 983.0 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.80 (s, 1H) , 8.50 (s, 1H) , 8.11 (s, 1H) , 7.89 (s, 1H) , 7.70 (s, 1H) , 7.59-7.50 (m, 3H) , 7.40-7.32 (m, 2H) , 7.26-7.18 (m, 2H) , 7.18-7.10 (m, 1H) , 6.70 (d, J = 10Hz, 1H) , 6.06 (d, J = 7.5Hz, 1H) , 4.91--4.88 (m, 1H) , 4.17-4.05 (m, 4H) , 3.90-3.80 (m, 1H) , 3.75 –3.70 (m, 2H) , 3.60-3.55 (m, 2H) , 3.53-3.51 (m, 2H) , 3.48-3.41 (m, 2H) , 3.05 –2.98 (m, 2H) , 2.87-2.69 (m, 6H) , 2.23-2.10 (m, 3H) , 1.89-1.75 (m, 4H) , 1.49-1.25 (m, 2H) .
The inhibition rate of the title compound of Example 18 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.0%and 99.4%, respectively.
Example 19: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (4- (3- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) propoxy) butyramido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 14. MS (ESI) m/z: 997.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.42 (s, 1H) , 8.27 (s, 1H) , 8.05 (s, 1H) , 7.84 (s, 1H) , 7.76 (s, 1H) , 7.71 –7.55 (m, 3H) , 7.43 –7.36 (m, 2H) , 7.26-7.18 (m, 2H) , 7.16 (dd, J = 8.3, 2.3 Hz, 1H) , 6.83 (d, J = 10.0 Hz, 1H) , 5.84 (d, J = 7.8 Hz, 1H) , 4.93 –4.86 (m, 1H) , 4.24 –4.05 (m, 4H) , 4.02-3.89 (m, 1H) , 3.76 (t, J = 4.6 Hz, 2H) , 3.57 (t, J = 6.3 Hz, 2H) , 3.52 –3.36 (m, 4H) , 3.12 –3.04 (m, 2H) , 2.94 –2.63 (m, 6H) , 2.23 (t, J = 7.2 Hz, 2H) , 2.16 –2.09 (m, 1H) , 2.06 –1.94 (m, 2H) , 1.90 –1.79 (m, 4H) , 1.49 –1.41 (m, 2H) .
The inhibition rate of the title compound of Example 19 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 98.9%and 99.0%, respectively.
Example 20: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (5- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-5-yl) oxy) ethoxy) ethoxy) pentanamido) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 14. MS (ESI) m/z: 997.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.50 (s, 1H) , 8.31 (s, 1H) , 8.05 (s, 1H) , 7.84 (s, 1H) , 7.76 (s, 1H) , 7.70 –7.56 (m, 3H) , 7.45 –7.36 (m, 2H) , 7.29 –7.22 (m, 2H) , 7.16 (dd, J = 8.3, 2.3 Hz, 1H) , 6.82 (d, J = 9.9 Hz, 1H) , 5.84 (d, J = 7.9 Hz, 1H) , 4.94 –4.85 (m, 1H) , 4.24 –4.06 (m, 4H) , 4.03 –3.90 (m, 1H) , 3.82 (t, J = 4.6 Hz, 2H) , 3.69 –3.63 (m, 2H) , 3.60 –3.53 (m, 2H) , 3.47 (t, J = 6.0 Hz, 2H) , 3.12 –3.02 (m, 2H) , 2.93 –2.63 (m, 6H) , 2.21 –2.08 (m, 3H) , 2.03 –1.94 (m, 2H) , 1.72 –1.62 (m, 2H) , 1.60 –1.53 (m, 2H) , 1.52 –1.40 (m, 2H) .
The inhibition rate of the title compound of Example 20 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.4%and 99.4%, respectively.
Example 21: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Step 1: tert-Butyl 4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentyl) oxy) piperidin-1-carboxylate
To a 50 mL reaction flask were added tert-butyl 4- ( (5-bromopentyl) oxy) piperidin-1-carboxylate (370 mg, 1.06 mmol) , DMF (5 mL) , 2- (2, 6-dioxopiperidin-3-yl) -4-hydroxyisoindolin-1, 3-dione (376 mg, 1.37 mmol) and Et3N (320 mg, 3.17 mmol) . The mixture was heated to 70℃ and stirred for 3 hr. After completion of the reaction, the reaction mixture was poured into water (80 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product 21-1 (400 mg, yield: 69.7%) . MS (ESI) m/z: 444.1 [M+H-100] +.
Step 2: 2- (2, 6-Dioxopiperidin-3-yl) -4- ( (5- (piperidin-4-yloxy) pentyl) oxy) isoindolin-1, 3-dione
In a 50 mL reaction flask, tert-butyl 4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentyl) oxy) piperidin-1-carboxylate (400 mg, 0.74 mmol) was dissolved in DCM (10.0 mL) and then TFA (6.0 mL) was added. The mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and adjusted to pH = 9-10 with 5%Na2CO3 aqueous solution.
The aqueous phase was extracted with EtOAc (100mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure, to provide 330 mg of the target compound as oil, which was directly used in the next step. MS (ESI) m/z: 444.1 [M+H] +.
Step 3: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) pentyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Under an atmosphere of nitrogen, N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (364 mg, 0.74 mmol) , 2- (2, 6-dioxopiperidin-3-yl) -4- ( (5- (piperidin-4-yloxy) pentyl) oxy) isoindolin-1, 3-dione (330 mg, 0.74 mmol) , Et3N (301 mg, 2.98 mmol) were dissolved in DMF (3mL) . The mixture was heated to 95℃ and stirred for 5 hr. After completion of the reaction, the system was cooled to room temperature. The reaction mixture was poured into water (50mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (50mg, yield: 7.5%) as a yellow solid. MS (ESI) m/z: 896.1 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H) , 8.20 (s, 1H) , 8.03 (s, 1H) , 7.86 (s, 1H) , 7.70 (s, 1H) , 7.65 –7.53 (m, 2H) , 7.42 –7.35 (m, 3H) , 7.17 (d, J = 8.4 Hz, 1H) , 6.90 (d, J = 9.2 Hz, 1H) , 4.82 –4.76 (m, 1H) , 4.24 –4.06 (m, 3H) , 3.87 –3.84 (m, 2H) , 3.58 –3.52 (m, 3H) , 3.37 –3.30 (m, 2H) , 2.92 –2.60 (m, 6H) , 2.03 –1.72 (m, 4H) , 1.42 –1.20 (m, 6H) .
The inhibition rate of the title compound of Example 21 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 99.7%.
Example 22: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (5- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) pentyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 21. MS (ESI) m/z: 895.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.21 (s, 1H) , 8.05 (s, 1H) , 7.83 (s, 1H) , 7.70 (s, 1H) , 7.61 (d, J = 7.2 Hz, 1H) , 7.52 (s, 1H) , 7.42 –7.35 (m, 3H) , 7.26 –7.24 (m, 1H) , 7.09 (d, J = 6.8 Hz, 1H) , 6.89 (s, 1H) , 6.82 (d, J = 8.1 Hz, 1H) , 4.91 –4.79 (m, 1H) , 3.80 –3.75 (m, 4H) , 3.58 –3.25 (m, 4H) , 2.78 –2.60 (m, 5H) , 2.03 –1.70 (m, 4H) , 1.46 –1.33 (m, 6H) .
The inhibition rate of the title compound of Example 22 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 98.0%.
Example 23: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (9- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) nonyl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 21. MS (ESI) m/z: 951.2 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H) , 8.05 (s, 1H) , 7.83 (s, 1H) , 7.75 (s, 1H) , 7.63 –7.55 (m, 2H) , 7.42 –7.35 (m, 3H) , 7.24 (d, J = 7.7 Hz, 1H) , 7.12 (d, J = 7.1 Hz, 1H) , 6.87 –6.81 (m, 2H) , 4.91 –4.81 (m, 1H) , 3.92 –3.84 (m, 2H) , 3.78 –3.69 (m, 2H) , 3.58 –3.24 (m, 5H) , 2.92 –2.60 (m, 6H) , 2.03 –1.82 (m, 4H) , 1.69 –1.40 (m, 5H) , 1.39 –1.21 (m, 9H) .
Example 24: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Step 1: 4- ( (7-Bromoheptyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione
At room temperature, to a 25 mL reaction flask were added stepwise 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (110 mg, 0.40 mmol) , NMP (2 mL) , 1, 7-dibromoheptane (156 mg, 0.60 mmol) and K2CO3 (139 mg, 1.00 mmol) . The mixture was stirred at room temperature and reacted for 3 hr. After completion of the reaction, the reaction mixture was poured into water (80 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) = 1: 1) to provide the product 24-1 (80 mg, yield: 44.1%) , as an oil. MS (ESI) m/z: 450.1 [M+H] +.
Step 2: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) heptyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
At room temperature, to a 25 mL reaction flask were added stepwise 4- ( (7-bromoheptyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (80 mg, 0.18 mmol) , DMF (2 mL) , N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (113 mg, 0.18 mmol) and K2CO3 (61mg, 0.44 mmol) . The mixture was stirred at room temperature and reacted for 3 hr. After completion of the reaction, the reaction mixture was poured into water (80 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (35 mg, yield: 19.6%) as a yellow solid. MS (ESI) m/z: 1006.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H) , 8.06 (s, 1H) , 7.86 (s, 1H) , 7.75 (s, 1H) , 7.68 –7.62 (m, 2H) , 7.42 –7.35 (m, 3H) , 7.26 –7.24 (m, 1H) , 7.11 (d, J = 5.5 Hz, 1H) , 6.89 –6.85 (m, 2H) , 4.91 –4.79 (m, 1H) , 3.80 –3.75 (m, 5H) , 3.68 –3.65 (m, 4H) , 3.37 –2.64 (m, 10H) , 2.45 –2.08 (m, 2H) , 1.96 –1.46 (m, 9H) , 1.40 –1.22 (m, 9H) .
The inhibition rate of the title compound of Example 24 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 90.8%and 99.7%, respectively.
Example 25: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (1- (7- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) heptyl) piperidin-4-yl) oxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 24. MS (ESI) m/z: 1007.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.58 (s, 1H) , 8.05 (s, 1H) , 7.88 (s, 1H) , 7.77 (s, 1H) , 7.68 –7.59 (m, 3H) , 7.42 –7.35 (m, 3H) , 7.26 –7.24 (m, 1H) , 7.19 (d, J = 8.5 Hz, 1H) , 6.85 (d, J = 9.9 Hz, 1H) , 4.93 (dd, J = 11.8, 5.1 Hz, 1H) , 4.16 –4.12 (m, 2H) , 3.80 –3.70 (m, 3H) , 3.68 –3.65 (m, 1H) , 3.37 –2.88 (m, 5H) , 2.85 –2.61 (m, 8H) , 2.45 –2.08 (m, 3H) , 1.96 –1.46 (m, 8H) , 1.40 –1.20 (m, 9H) .
The inhibition rate of the title compound of Example 25 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.6%and 99.4%, respectively.
Example 26: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) propoxy) ethoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 4. MS (ESI) m/z: 999.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.52 (s, 1H) , 8.05 (s, 1H) , 7.86 (s, 1H) , 7.74 (s, 1H) , 7.64 (d, J = 9.9 Hz, 1H) , 7.59 (d, J = 7.7 Hz, 1H) , 7.45 (t, J = 7.8 Hz, 1H) , 7.41 –7.33 (m, 2H) , 7.23 (t, J = 7.7 Hz, 1H) , 7.02 (d, J = 7.1 Hz, 1H) , 6.87 (t, J = 9.0 Hz, 2H) , 6.42 (t, J = 5.7 Hz, 1H) , 4.87 –4.79 (m, 1H) , 3.91 –3.85 (m, 2H) , 3.70 –3.62 (m, 10H) , 3.62 –3.52 (m, 4H) , 3.41 –3.26 (m, 4H) , 3.00 –2.59 (m, 7H) , 2.11 –2.05 (m, 1H) , 1.98 –1.84 (m, 4H) , 1.74 –1.67 (m, 2H) .
The inhibition rate of the title compound of Example 26 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.9%and 99.3%, respectively.
Example 27: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethoxy) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 21, MS (ESI) m/z: 986.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.36 (s, 1H) , 8.14 (s, 1H) , 8.05 (s, 1H) , 7.86 (s, 1H) , 7.78 (d, J = 5.7 Hz, 1H) , 7.69 (d, J = 9.8 Hz, 1H) , 7.63 –7.58 (m, 1H) , 7.56 (d, J = 7.7 Hz, 1H) , 7.46 –7.35 (m, 3H) , 7.25 –7.16 (m, 2H) , 6.88 (d, J = 9.9 Hz, 1H) , 4.92 –4.86 (m, 1H) , 4.25 (t, J = 4.5 Hz, 2H) , 3.92 –3.81 (m, 4H) , 3.70 –3.56 (m, 13H) , 3.39 –3.28 (m, 2H) , 2.89 –2.66 (m, 6H) , 2.12–2.05 (m, 1H) , 1.99–1.88 (m, 2H) , 1.76 –1.68 (m, 2H) .
The inhibition rate of the title compound of Example 27 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.2%and 99.1%, respectively.
Example 28: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) amino) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Step 1: 3- ( (6- (4- ( (2- (2- (2- (2-Bromoethoxy) ethoxy) ethoxy) ethyl) amino) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
To a 50 mL reaction flask were added 3- ( (6- (4-aminopiperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide (200.0 mg, 0.36 mmol) , DMF (3.0 mL) , 1-bromo-2- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) ethane (115.2 mg, 0.36 mmol) and K2CO3 (99.4 mg, 0.72 mmol) . The mixture was stirred at room temperature and reacted for 16 hr. After completion of the reaction, the reaction mixture was poured into water (80 mL) , and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product 28-1 (180 mg, yield: 63.1%) as a white solid. MS (ESI) m/z: 791, 793 [M+H] +.
Step 2: tert-Butyl (2- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) ethyl) (1- (3- ( (3- ( (3-chloro-5-trifluoromethylphenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) carbamate
In a 50 mL reaction flask, 3- ( (6- (4- ( (2- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) ethyl) amino) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide (180.0 mg, 0.23 mmol) was dissolved in THF (3.0 mL) , and then (Boc) 2O (99.1 mg, 0.46 mmol) was added. The mixture was stirred at room temperature and reacted for 16 hr. After completion of the reaction, the reaction mixture was poured into water (50 mL) , and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 50: 1) to provide the product 28-2 (160 mg, yield: 78.2%) as a white solid. MS (ESI) m/z: 791, 793 [M+H-100] +.
Step 3: tert-Butyl (1- (3- ( (3- ( (3-chloro-5-trifluoromethylphenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) carbamate
tert-Butyl (2- (2- (2- (2-bromoethoxy) ethoxy) ethoxy) ethyl) (1- (3- ( (3- ( (3-chloro-5-trifluoromethylphenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) carbamate (160.0 mg, 0.18 mmol) , 4-amino-2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (49.1 mg, 0.18 mmol) and K2CO3 (49.7 mg, 0.36 mmol) were dispersed in DMF (5.0 mL) . The mixture was stirred at room temperature and reacted for 16 hr. After completion of the reaction, the reaction mixture was poured into water (100 mL) , and the aqueous phase was extracted with EtOAc (100mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 40: 1) to provide the product 28-3 (86.0 mg, yield: 44.1%) as a yellow solid. MS (ESI) m/z: 1084.3 [M+H] +.
Step 4: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- ( (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) amino) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
tert-Butyl (1- (3- ( (3- ( (3-chloro-5-trifluoromethylphenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) (2- (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethoxy) ethyl) carbamate (86.0 mg, 0.079 mmol) was dissolved in DCM (1.0 mL) , and then TFA (2.0 mL) was added. The mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and adjusted to pH = 9-10 with 5%Na2CO3 aqueous solution. The aqueous phase was extracted with EtOAc (100mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (30.0 mg, yield: 38.6%) as a yellow solid. MS (ESI) m/z: 984.0 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.93 (s, 1H) , 8.09 (s, 1H) , 7.93 (s, 1H) , 7.69 (s, 1H) , 7.59-7.55 (m, 2H) , 7.37 (s, 2H) , 7.21 (s, 1H) , 7.05 (s, 1H) , 6.84-6.80 (m, 2H) , 4.92 –4.86 (m, 1H) , 4.17-4.12 (m, 3H) , 3.95-3.91 (m, 2H) , 3.70-3.55 (m, 13H) , 2.96-2.82 (m, 3H) , 2.77-2.58 (m, 5H) , 2.12-1.95 (m, 4H) , 1.80-1.54 (m, 2H) .
The inhibition rate of the title compound of Example 28 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 98.6%.
Example 29: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- ( (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethoxy) ethyl) amino) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 28. MS (ESI) m/z: 985.3 [M+H] +. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H) , 10.93 (s, 1H) , 8.16–8.11 (m, 2H) , 7.97 –7.86 (m, 2H) , 7.77 (t, J = 7.9, 1H) , 7.68 (d, J = 7.6 Hz, 1H) , 7.59 –7.54 (m, 2H) , 7.49 (d, J = 8.5 Hz, 1H) , 7.46–7.38 (m, 2H) , 7.30 (d, J = 10.0 Hz, 1H) , 5.10–5.03 (m, 1H) , 4.36 –4.32 (m, 2H) , 4.07 –3.99 (m, 1H) , 3.96 –3.89 (m, 2H) , 3.83 –3.79 (m, 2H) , 3.75 –3.70 (m, 2H) , 3.62 –3.51 (m, 7H) , 3.03 –2.96 (m, 4H) , 2.93 –2.82 (m, 1H) , 2.68 –2.51 (m, 5H) , 2.07 –1.96 (m, 2H) , 1.94 –1.86 (m, 2H) , 1.56 –1.44 (m, 2H) .
The inhibition rate of the title compound of Example 29 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 98.8%.
Example 30: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- ( (2- (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethoxy) ethyl) amino) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 28. MS (ESI) m/z: 984.2 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 9.22 –8.84 (m, 2H) , 8.18 (s, 1H) , 7.99 (s, 1H) , 7.72 (s, 1H) , 7.63 (d, J = 7.7 Hz, 1H) , 7.48 –7.32 (m, 3H) , 7.31 –7.27 (m, 1H) , 7.10 (d, J = 7.0 Hz, 1H) , 6.91 –6.77 (m, 2H) , 5.43 –5.18 (m, 2H) , 4.98 –4.92 (m, 1H) , 4.01 –3.72 (m, 8H) , 3.70 –3.45 (m, 8H) , 3.28 –3.22 (m, 4H) , 2.93 –2.61 (m, 6H) , 2.11 –1.84 (m, 4H) , 1.76 –1.67 (m, 2H) .
The inhibition rate of the title compound of Example 30 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 98.7%.
Example 31: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- ( (2- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethoxy) ethyl) amino) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 28. MS (ESI) m/z: 984.2 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 9.11 (s, 1H) , 8.14 (s, 1H) , 7.99 (s, 1H) , 7.78 (s, 1H) , 7.69 (d, J = 9.8 Hz, 1H) , 7.60 (d, J = 7.7 Hz, 1H) , 7.45 (d, J = 7.7 Hz, 1H) , 7.37 –7.34 (m, 2H) , 7.31 –7.27 (m, 1H) , 7.10 –7.05 (m, 2H) , 6.90 –6.79 (m, 2H) , 5.37 –5.34 (m, 2H) , 5.03 –4.88 (m, 1H) , 4.08 –3.95 (m, 1H) , 3.91 –3.73 (m, 5H) , 3.71 –3.44 (m, 10H) , 3.21 –3.10 (m, 4H) , 2.83 –2.55 (m, 6H) , 2.09 –1.86 (m, 4H) , 1.44 –1.40 (m, 2H) .
The inhibition rate of the title compound of Example 31 on Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM was 98.0%.
Example 32: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) oxy) ethyl) piperazin-1-yl) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 21. MS (ESI) m/z: 1010.2 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.79 (s, 1H) , 8.44 (s, 1H) , 8.10 (s, 1H) , 7.90 (s, 1H) , 7.75 (s, 1H) , 7.68 –7.59 (m, 2H) , 7.53 (d, J = 7.7 Hz, 1H) , 7.47 –7.31 (m, 3H) , 7.21 (t, J = 7.7 Hz, 1H) , 7.13 (d, J = 8.3 Hz, 1H) , 6.87 (d, J = 9.9 Hz, 1H) , 4.93 –4.87 (m, 1H) , 4.34 –4.05 (m, 3H) , 3.92 –3.79 (m, 2H) , 3.73 –3.47 (m, 8H) , 3.40 –3.21 (m, 2H) , 2.98 –2.53 (m, 15H) , 2.18 –1.85 (m, 4H) , 1.76 –1.63 (m, 2H) .
The inhibition rate of the title compound of Example 32 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 98.8%and 98.8%, respectively.
Example 33: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (2- (4- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) piperazin-1-yl) ethoxy) ethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
The title compound was obtained following the method of Example 5. MS (ESI) m/z: 1009.3 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 8.33 –8.19 (m, 1H) , 8.09 (s, 1H) , 7.90 (s, 1H) , 7.78 (s, 1H) , 7.71 –7.55 (m, 2H) , 7.50 –7.32 (m, 3H) , 7.26 –7.15 (m, 1H) , 7.06 (d, J = 7.2 Hz, 1H) , 6.87 (d, J = 9.8 Hz, 1H) , 6.79 (d, J = 8.5 Hz, 1H) , 6.62 –6.58 (m, 1H) , 5.00 –4.77 (m, 1H) , 4.23 –3.99 (m, 1H) , 3.90 –3.52 (m, 9H) , 3.43 –3.11 (m, 4H) , 2.93 –2.40 (m, 16H) , 2.19 –1.89 (m, 4H) , 1.60 –1.47 (m, 2H) .
The inhibition rate of the title compound of Example 33 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.8%and 99.4%, respectively.
Example 34: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (9- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoindolin-4-yl) amino) ethyl) -3, 9-diazaspiro [5.5] undecan-3-yl) -2-oxoethoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
Step 1: Ethyl 2- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) acetate
Ethyl 2- (piperidin-4-yloxy) acetate (100 mg, 0.53 mmol) , K2CO3 (200 mg, 1.06 mmol) and N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (313 mg, 0.64 mmol) were dispersed in DMF (4 mL) . The mixture was heated to 100℃ and reacted for 12 h. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (100mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 25: 1) to provide the product (100 mg, yield 29.2%) as a yellow solid. MS (ESI) m/z: 640.2 [M+H] +.
Step 2: 2- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) acetic acid
Ethyl 2- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) acetate (100 mg, 0.15 mmol) was dissolved in a mixture of MeOH (2 mL) and water (2 mL) , and then anhydrous LiOH (54 mg, 0.574 mmol) was added. The mixture was stirred at room temperature and reacted for 2 hr. After completion of the reaction, the reaction mixture was diluted with water (20 mL) , and adjusted to pH = 5 with 1 M hydrochloric acid solution, and the aqueous phase was extracted with EtOAc
(50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (72 mg, yield 75.3%) as a pale yellow solid. MS (ESI) m/z: 612.2 [M+H] +.
Step 3: tert-Butyl 9- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -3, 9-diazaspiro [5.5] undecan-3-carboxylate
To a 25 mL round-bottom flask were added tert-butyl 9- (2-aminoethyl) -3, 9-diazaspiro [5.5] undecan-3-carboxylate (60 mg, 0.2 mmol) , DIPEA (120 mg, 0.6 mmol) , 2- (2, 6-oxopiperidin-3-yl) -4-fluoroisoindolin-1, 3-dione (83.5 mg, 0.3 mmol) and DMSO (3 mL) . The mixture was heated to 100℃ and stirred for 4 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product (53 mg, yield 47.5%) as a pale yellow solid. MS (ESI) m/z: 554.3 [M+H] +.
Step 4: 4- ( (2- (3, 9-Diazaspiro [5.5] undecan-3-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione
tert-Butyl 9- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoisoindolin-4-yl) amino) ethyl) -3, 9-diazaspiro [5.5] undecan-3-carboxylate (53 mg, 0.095 mmol) was dissolved in a solution of HCl/MeOH (6M, 5 mL) . The mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and adjusted to pH = 9-10 with 5%Na2CO3 aqueous solution, and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure, to provide 42 mg of the target compound as a yellow solid, which was directly used in the next step. MS (ESI) m/z: 454.3 [M+H] +.
Step 5: N- (3-Chloro-5- (trifluoromethyl) phenyl) -3- ( (6- (4- (2- (9- (2- ( (2- (2, 6-dioxopiperidin-3-yl) -1, 3-dioxoindolin-4-yl) amino) ethyl) -3, 9-diazaspiro [5.5] undecan-3-yl) -2-oxoethoxy) piperidin-1-
yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide
In a 25mL round-bottom flask were added 2- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) acetic acid (50 mg, 0.08 mmol) , HATU (80 mg, 0.21mmol) , DMF (3 mL) , Et3N (24 mg, 0.24mmol) and 4- ( (2- (3, 9-diazaspiro [5.5] undecan-3-yl) ethyl) amino) -2- (2, 6-dioxopiperidin-3-yl) isoindolin-1, 3-dione (40.76 mg, 0.089 mmol) . The mixture was stirred at room temperature and reacted for 2 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product (25 mg, yield 30%) as a pale yellow solid. MS (ESI) m/z: 1047.4 [M+H] +. 1H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H) , 10.90 (s, 1H) , 8.15 –8.11 (m, 2H) , 7.94 –7.87 (m, 2H) , 7.68 (d, J = 7.8 Hz, 1H) , 7.63 –7.51 (m, 3H) , 7.45 –7.40 (m, 2H) , 7.35 –7.29 (m, 2H) , 5.13 –4.98 (m, 1H) , 4.18 –4.14 (m, 2H) , 4.00 –3.85 (m, 2H) , 3.78 –3.58 (m, 2H) , 3.51 –3.30 (m, 9H) , 3.15 –2.98 (m, 1H) , 2.98 –2.80 (m, 1H) , 2.71 –2.56 (m, 5H) , 2.43 –2.29 (m, 1H) , 2.09 –1.78 (m, 6H) , 1.66 –1.30 (m, 10H) .
The inhibition rate of the title compound of Example 34 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 99.0%and 98.7%, respectively.
Example 35: (2S, 4R) -1- ( (S) -2- (8- (4- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -8-oxooctanamido) -3, 3-dimethylbutyramido) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
Step 1: Methyl 8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctoate
8-Methoxy-8-oxooctanoic acid (126.7 mg, 0.67 mmol) was dissolved in DMF (5.0 mL) , and then HATU (381.9 mg, 1.0 mmol) and Et3N (135.3 mg, 2 mmol) were added. The mixture was stirred at room temperature and reacted for 1 hr. Then, (2S, 4R) -1- ( (S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide (126.7 mg, 0.67 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc (v/v) = 1: 1) to provide the product (260 mg, yield 63%) as a white solid. MS (ESI) m/z: 615.3 [M+H] +.
Step 2: 8- ( ( (S) -1- ( (2S, 4R) -4-Hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctanoic acid
Methyl 8- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctoate (260 mg, 0.42 mmol) was dissolved in a mixture of MeOH (5 mL) and water (2 mL) , and then
anhydrous LiOH (177.8 mg, 4.2 mmo) was added. The mixture was stirred at room temperature and reacted for 3 hr. After completion of the reaction, the reaction mixture was diluted with water (50 mL) , and adjusted to pH = 5 with 2M hydrochloric acid solution. The aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (190 mg, yield 75.3%) as a white solid. MS (ESI) m/z: 601.3 [M+H] +.
Step 3: (2S, 4R) -1- ( (S) -2- (8- (4- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -8-oxooctanamido) -3, 3-dimethylbutyramido) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
8- ( ( (S) -1- ( (2S, 4R) -4-Hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -8-oxooctanoic acid (80.0 mg, 0.13 mmol) was dissolved in DMF (2.0 mL) , and then HATU (76.0 mg, 0.20 mmol) and Et3N (26.3 mg, 0.26 mmol) were added. The mixture was stirred at room temperature and reacted for 1 hr. Then, N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methyl-3- ( (6- (4- (piperidin-4-yloxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) benzamide (84.8 mg, 0.13 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product (32 mg, yield 20%) as a white solid. MS (ESI) m/z: 1217 [M-H] -. 1HNMR (500 MHz, CDCl3) δ 8.77-8.65 (m, 2H) , 8.07 (s, 1H) , 7.95-7.88 (m, 2H) , 7.61 (s, 1H) , 7.59 (s, 1H) , 7.46-7.28 (m, 8H) , 7.05 (d, J = 6.0, Hz, 1H) , 6.22 (d, J = 8.5, Hz, 1H) , 5.07-5.04 (m, 1H) , 4.72 (s, 1H) , 4.57-4.47 (m, 2H) , 4.10-
4.08 (m, 1H) , 3.86-3.72 (m, 2H) , 3.69-3.53 (m, 8H) , 3.46-3.40 (m, 2H) , 3.29-3.24 (m, 2H) , 2.67 (s, 3H) , 2.51-2.48 (m, 5H) , 2.25-2.20 (m, 5H) , 1.80-1.71 (m, 4H) , 1.45-1.39 (m, 5H) , 1.29-1.25 (m, 6H) , 1.01 (s, 9H) .
The inhibition rate of the title compound of Example 35 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 89.2%and 99.5%, respectively.
Example 36: (2S, 4R) -1- ( (S) -2- (9- (4- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) piperidin-1-yl) -9-oxononylamido) -3, 3-dimethylbutyramido) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
The title compound was obtained following the method of Example 35. MS (ESI) m/z: 1231 [M-H] -. 1H NMR (500 MHz, CDCl3) δ 9.24-9.22 (m, 1H) , 8.68 (s, 1H) , 8.17-7.88 (m, 3H) , 7.70 (s, 1H) , 7.52-7.50 (m, 3H) , 7.46-7.37 (m, 6H) , 7.07-7.03 (m, 1H) , 6.24-6.20 (m, 1H) , 5.07-5.04 (m, 1H) , 4.72 (s, 1H) , 4.57-4.48 (m, 2H) , 4.10-4.08 (m, 1H) , 3.86-3.42 (m, 8H) , 3.27-3.22 (m, 2H) , 2.67 (s, 3H) , 2.57-2.42 (m, 5H) , 2.40-2.20 (m, 9H) , 1.97-1.91 (m, 4H) , 1.45-1.40 (m, 6H) , 1.25-1.20 (m, 7H) , 1.10-1.0 (m, 9H) .
The inhibition rate of the title compound of Example 36 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 78.7%and 99.5%, respectively.
Example 37: N1- (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) -N9- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) nonandiamide
Step 1: Methyl 9- ( (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -9-oxononanoate
Methyl 9-oxo-9- ( (3- (piperidin-4-yloxy) propyl) amino) nonanoate (360 mg, 1.05 mmol) , N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (617 mg, 1.26 mmol) and K2CO3 (200 mg, 2.1 mmol) were dispersed in DMF (5 mL) . The mixture was heated to 100℃, stirred and reacted for 12 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 50: 1) to provide the product (154 mg, yield 20%) as a pale yellow solid. MS (ESI) m/z: 795.3 [M+H] +.
Step 2: 9- ( (3- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -9-oxononanoic acid
Methyl 9- ( (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -9-oxononanoate (154 mg, 0.197 mmol) was dissolved in a mixture of MeOH (4 mL) and water (4 mL) , and then anhydrous LiOH (54 mg, 0.574 mmol) was added. The mixture was stirred at room temperature and reacted for 2 hr. After completion of the reaction, the reaction mixture was diluted with water (50 mL) , adjusted to pH = 5 with 1 M hydrochloric acid solution, and the aqueous phase
was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product (130 mg, yield 84.5%) as a pale yellow solid. MS (ESI) m/z: 601.3 [M+H] +.
Step 3: N1- (3- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) -N9- ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) nonandiamide
9- ( (3- ( (1- (3- ( (3- ( (3-Chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -9-oxononanoic acid (130 mg, 0.166 mmol) was dissolved in DMF (4.0 mL) , and then HATU (95.0 mg, 0.25 mmol) and Et3N (50 mg, 0.50 mmol) were added. The mixture was stirred at room temperature and reacted for 1 hr. Then (2S, 4R) -1- ( (S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide (84.91mg, 0.216 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 15: 1) to provide the product (31 mg, yield 16%) as a white solid. MS (ESI) m/z: 1027.5 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 9.25 (s, 1H) , 8.65 (s, 1H) , 8.15 (s, 1H) , 7.96 (s, 1H) , 7.87 (d, J = 9.9 Hz, 1H) , 7.80 (s, 1H) , 7.60 (d, J = 7.7 Hz, 1H) , 7.49 –7.37 (m, 9H) , 7.02 (d, J = 9.9 Hz, 1H) , 6.26 (d, J = 8.8 Hz, 1H) , 6.15 (s, 1H) , 5.07-
5.04 (m, 1H) , 4.70 (t, J = 8.2 Hz, 1H) , 4.57 (d, J = 8.8 Hz, 1H) , 4.50 –4.45 (m, 1H) , 4.01 (d, J = 11.4 Hz, 1H) , 3.86-3.80 (m, 2H) , 3.62 –3.51 (m, 5H) , 3.39 (t, J = 10.5 Hz, 2H) , 3.32 (q, J = 5.9 Hz, 2H) , 2.69 (s, 3H) , 2.51 (s, 3H) , 2.45 –2.36 (m, 1H) , 2.12 –1.98 (m, 4H) , 1.80-1.71 (m, 4H) , 1.45-1.39 (m, 9H) , 1.20 –1.12 (m, 6H) , 1.02 (s, 9H) .
The inhibition rate of the title compound of Example 37 on Ba/F3-LMNA-NTRK1 and Ba/F3-LMNA-NTRK1-G667C at the concentration of 1 μM were 88.0%and 99.7%, respectively.
Example 38: (2S, 4R) -1- ( (S) -2- (tert-Butyl) -16- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) -4, 12-dioxo-6-oxa-3, 9, 13-triazahexadecanoyl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
Step 1: tert-Butyl (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) carbamate
tert-Butyl (3- (piperidin-4-yloxy) propyl) carbamate (210 mg, 0.81 mmol l) , N- (3-chloro-5- (trifluoromethyl) phenyl) -3- ( (6-chloroimidazo [1, 2-b] pyridazin-3-yl) ethynyl) -2-methylbenzamide (398 mg, 0.81 mmol) and K2CO3 (337 mg, 2.44 mmol) were dispersed in DMF (5 mL) . The mixture was heated to 100℃, stirred and reacted for 18 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 20: 1) to provide the product (320 mg, yield 55%) as a yellow solid. MS (ESI) m/z: 611.2 [M+H-100] +.
Step 2: 3- ( (6- (4- (3-Aminopropoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide
tert-Butyl (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) carbamate (320 mg, 0.45 mmol) was dissolved in DCM (3 mL) , and then TFA (3 mL) was added. The mixture was stirred at room temperature and reacted for 2 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and adjusted to pH = 9-10 with 5%Na2CO3 aqueous solution. The aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure, to provide 260 mg of the target compound as a yellow solid, which was directly used in the next step. MS (ESI) m/z: 611.2 [M+H] +.
Step 3: Ethyl 3- ( (tert-butoxycarbonyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) amino) propionate
In a 25 mL round-bottom flask were added 2- (2- ( (tert-butoxycarbonyl) (3-ethoxy-3-oxopropyl) amino) ethoxy) acetic acid (160 mg, 0.50 mmol) , (2S, 4R) -1- ( (S) -2-amino-3, 3-dimethylbutyryl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide (245 mg, 0.55 mmol) , Et3N (177 mg, 1.75 mmol) and DMF (4.0 mL) . The mixture was stirred until completely dissolved, and then HATU (286 mg, 0.75 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (230 mg, yield 62%) as a yellow solid. MS (ESI) m/z: 646.4 [M+H-100] +.
Step 4: 3- ( (tert-Butoxycarbonyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -
2-oxoethoxy) ethyl) amino) propanoic acid
Ethyl 3- ( (tert-butoxycarbonyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) amino) propionate (230 mg, 0.31 mmol) was dissolved in a mixture of MeOH (2 mL) and water (2 mL) , and then LiOH. H2O (130 mg, 3.08 mmol) was added. The mixture was stirred at room temperature and reacted for 2 hr. After completion of the reaction, the reaction mixture was diluted with water (50 mL) , and adjusted to pH = 3-4 with 2M hydrochloric acid solution, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure to provide the target product as a solid, which was directly used in the next step. MS (ESI) m/z: 618.3 [M+H-100] +.
Step 5: tert-Butyl (3- ( (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -3-oxopropyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) carbamic acid
3- ( (tert-Butoxycarbonyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) amino) propanoic acid (125 mg, 0.17 mmol) was dissolved in DMF (4.0 mL) , and
then HATU (132 mg, 0.35 mmol) and Et3N (70 mg, 0.70 mmol) were added. The mixture was stirred at room temperature and reacted for 1 hr. Then, 3- ( (6- (4- (3-aminopropoxy) piperidin-1-yl) imidazo [1, 2-b] pyridazin-3-yl) ethynyl) -N- (3-chloro-5- (trifluoromethyl) phenyl) -2-methylbenzamide (128 mg, 0.21 mmol) was added. The resulting mixture was stirred at room temperature and reacted for 1 hr. After completion of the reaction, the reaction mixture was diluted with water, and the aqueous phase was extracted with EtOAc (80mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 10: 1) to provide the product (160 mg, yield70%) as a white solid. MS (ESI) m/z: 1210.5 [M+H-100] +.
Step 6: (2S, 4R) -1- ( (S) -2- (tert-Butyl) -16- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) -4, 12-dioxo-6-oxa-3, 9, 13-triazahexadecanoyl) -4-hydroxy-N- ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) pyrrolidin-2-carboxamide
tert-Butyl (3- ( (3- ( (1- (3- ( (3- ( (3-chloro-5- (trifluoromethyl) phenyl) carbamyl) -2-methylphenyl) ethynyl) imidazo [1, 2-b] pyridazin-6-yl) piperidin-4-yl) oxy) propyl) amino) -3-oxopropyl) (2- (2- ( ( (S) -1- ( (2S, 4R) -4-hydroxy-2- ( ( (S) -1- (4- (4-methylthiazol-5-yl) phenyl) ethyl) carbamyl) pyrrolidin-1-yl) -3, 3-dimethyl-1-oxobutan-2-yl) amino) -2-oxoethoxy) ethyl) carbamic acid (160 mg, 0.12 mmol) was dissolved in DCM (3 mL) , and then TFA (3 mL) was added. The mixture was stirred at room temperature and reacted for 2 hr. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with water, and adjusted to pH = 9-10 with 5%Na2CO3 aqueous solution, and the aqueous phase was extracted with EtOAc (50mL*3) . The organic phase was washed with saturated NaCl aqueous solution, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH (v/v) = 5: 1)
to provide the product (35 mg, yield 3.7%) . MS (ESI) m/z: 1210.4 [M+H] +. 1H NMR (500 MHz, CDCl3) δ 9.40 (s, 1H) , 8.64 (s, 1H) , 8.17 (s, 1H) , 7.95 (s, 1H) , 7.80 (s, 1H) , 7.73 (d, J = 9.8 Hz, 1H) , 7.63 –7.49 (m, 3H) , 7.43 –7.28 (m, 8H) , 7.21 (t, J = 7.7 Hz, 1H) , 6.89 (d, J = 9.9 Hz, 1H) , 5.05 –4.98 (m, 1H) , 4.53 –4.48 (m, 2H) , 4.37 –4.34 (m, 1H) , 3.99 –3.93 (m, 1H) , 3.90 –3.79 (m, 3H) , 3.73 –3.67 (m, 1H) , 3.65 –3.18 (m, 12H) , 2.89 –2.68 (m, 4H) , 2.64 (s, 3H) , 2.57 –2.45 (m, 4H) , 2.35 –2.18 (m, 2H) , 2.10 –1.89 (m, 4H) , 1.79 –1.65 (m, 2H) , 1.47 (d, J = 6.9 Hz, 3H) , 0.97 (s, 9H) .
The foregoing descriptions are only preferred examples of the present invention and are not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.
Claims (17)
- A compound, characterized in that, said compound is a compound having a chemical structure of general Formula (I) :E3 ubiquitin ligase ligand-L-tropomyosin-related kinase ligand (Ⅰ) ;in said E3 ubiquitin ligase ligand, said E3 ubiquitin ligase is selected from the group consisting of CRBN or vHL, the ligand of said vHL is selected from the group consisting of VH032 or an analogue thereof, the ligand of said CRBN is selected from the group consisting of Lenalidomide, Lenalidomide analogues, Pomalidomide, Pomalidomide analogues, Thalidomide or Thalidomide analogues;L is a linker;said tropomyosin-related kinase ligand is selected from the group consisting of a protein kinase inhibitor or a protein kinase inhibitor fragment, said tropomyosin-related kinase ligand functions at least via the binding to one of protein kinase, protein kinase mutation, protein kinase fusion and protein kinase deletion.
- The compound according to claim 1, characterized in that, said tropomyosin-related kinase ligand has a chemical structure of general Formula (II) :
wherein, R1 is H, halogen, C1-C6 alkyl, C1-C6 alkoxy or halogen-substituted C1-C6 alkyl; R2 is H, fluoro-substituted C1-C4 alkyl, substituted or unsubstituted 5-6 membered heterocyclyl containing 1-3 N ring atoms; R3 is H, halogen, amino or C1-C3 alkyl-substituted amino, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C1-C10 alkoxy, substituted or unsubstituted 5-10 membered heterocyclyl containing 1-3 N ring atoms, substituted or unsubstituted 5-10 membered heteroaryl containing 1-3 N ring atoms; R4 is C1-C6 alkyl;R5 is -NR6R7, wherein, each of R6 and R7 is independently selected from the group consisting of: - (CH2) mNR8R9, - (CH2) nCR10R11R12, - (CH2) pOR12, or R6 and R7 together with the nitrogen atom to which they attach to form a substituted or unsubstituted heteroatom-containing monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring; each of R8 and R9 is independently selected from the group consisting of: H, C1-C20 alkyl; or R8 and R9 together with the nitrogen atom to which they attach to form a substituted or unsubstituted monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring containing 1-3 heteroatoms; R10 and R11 together with the carbon atom to which they attach to form a substituted or unsubstituted monocyclic, fused cyclic, spiro cyclic or bridged cyclic ring containing 1-3 heteroatoms; R12 is selected from the group consisting of: H, C1-C20 alkyl; each of m, n, and p is independently selected from the group consisting of integers of 0-10. - The compound according to claim 2, characterized in that, said tropomyosin-related kinase ligand has a chemical structure of general Formula (Ⅱ1) :
wherein, t is 1, 2 or 3, X is H, Cl or Br. - The compound according to claim 3, characterized in that, said tropomyosin-related kinase ligand has any of the following structures:
- The compound according to claim 1, characterized in that, said L has a chemical structure of general Formula (Ⅲ) :
wherein, Y1 and Z1 independently are O, S or NH; W1 and W2 independently are absent, O, NH, C1-C6 linear alkyl, a1, b1, a2, b2, a3, a4 independently are positive integers of 0 to 20; Q1, Q2, Q3, Q4 independently are -CH2-, NH, and O; when W1, and W2 independently are NH or linear alkyl, they are optionally substituted by hydroxy, C1-C10 alkyl, C1-C6 alkoxy, or halogen;denotes an attachement point. - The compound according to claim 5, characterized in that, said L has any of the following structures:
- The compound according to claim 1, characterized in that, said L has a chemical structure of general Formula (Ⅳ) :
wherein, Y2 and Z2 are O, S or NH; W3, W4, and W5 independently are absent, O, NH, C1-C6 linear alkyl, orc, d, e, f, g, and h independently are positive integers of 0 to 20; M1 and M2 independently are -CH-or N; Q4, Q5, Q6, and Q7 independently are -CH2-, NH,or O. - The compound according to claim 7, characterized in that, said L has any of the following structures:
- The compound according to claim 1, characterized in that, said L has a chemical structure of general Formula (Ⅴ) :
wherein, Y3 and Z3 are O, S or NH; W6 and W7 are absent, O, NH, C1-C6 linear alkyl, ori and n' independently are positive integers of 0-16; M3 and M4 of the spiro cyclic moiety independently are selected from the group consisting of NH or CH; j, k, l, and m' independently are selected from the group consisting of 0, 1, 2, or 3; Q8 and Q9 independently are -CH2-, NH, or O. - The compound according to claim 9, characterized in that, said L has any of the following structures:
- The compound according to claims 5, 7 or 9, characterized in that, said C1-C6 linear alkyl is selected from the group consisting of any of the following groups:
- The compound according to claim 1, characterized in that, any of the following compounds are included:
- The compound according to any of claims 1-10 and 12, characterized in that, said compound further includes: a pharmaceutically acceptable salt, stereisomer, ester, prodrug, solvate and deuterated compound of said compound.
- A pharmaceutical composition, characterized in that, said pharmaceutical composition comprises the compound according to any of claims 1-13.
- Use of the compound according to any of claims 1-13 or the pharmaceutical composition according to claim 14 in the manufacture of a medicament for the prevention, diagonosis or treatment of protein kinase mediated diseases caused by the expression, mutation or fusion of a protein kinase.
- The use according to claim 15, characterized in that, said medicament is useful for the prevention, diagonosis or treatment of protein kinase mediated tumor, said tumor includes at least one of non-small cell lung cancer, breast cancer, colon cancer, prostate cancer, thyroid cancer, malignant melanoma, neuroblastoma and secretory carcinoma of breast.
- The use according to claim 15, characterized in that, the administration route of said medicament includes at least one of oral, intracutaneous injection, subcutaneous injection, application onto skin, parenteral, and rectal administration.
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| CN113278010A (en) * | 2021-06-01 | 2021-08-20 | 中国科学院上海有机化学研究所 | Protein kinase degradation agent and application thereof |
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| WO2017197051A1 (en) * | 2016-05-10 | 2017-11-16 | C4 Therapeutics, Inc. | Amine-linked c3-glutarimide degronimers for target protein degradation |
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