WO2022199503A1 - 杂环化合物治疗与激酶耐药突变相关的疾病的用途和方法 - Google Patents

杂环化合物治疗与激酶耐药突变相关的疾病的用途和方法 Download PDF

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WO2022199503A1
WO2022199503A1 PCT/CN2022/081890 CN2022081890W WO2022199503A1 WO 2022199503 A1 WO2022199503 A1 WO 2022199503A1 CN 2022081890 W CN2022081890 W CN 2022081890W WO 2022199503 A1 WO2022199503 A1 WO 2022199503A1
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compound
ret
alkyl
cancer
compounds
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French (fr)
Chinese (zh)
Inventor
陈忠辉
袁晓曦
雷冬梅
韩润丰
韩晓军
田强
宋宏梅
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to AU2022242476A priority Critical patent/AU2022242476A1/en
Priority to EP22774164.2A priority patent/EP4316490A4/en
Priority to US18/283,673 priority patent/US20250268897A1/en
Priority to JP2023557142A priority patent/JP2024511389A/ja
Priority to KR1020237025273A priority patent/KR20230159367A/ko
Priority to CA3210109A priority patent/CA3210109A1/en
Priority to CN202280011390.5A priority patent/CN116801882A/zh
Publication of WO2022199503A1 publication Critical patent/WO2022199503A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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 relates to the use of heterocyclic compounds in the manufacture of a medicament for the treatment or adjunctive treatment of diseases or conditions associated with RET (Rearranged during transfection) resistance mutations in individuals and methods of treatment using the heterocyclic compounds.
  • RET Rearranged during transfection
  • Protein kinases are a class of enzymes that catalyze protein phosphorylation reactions. By mediating cell signaling processes, protein phosphorylation regulates cellular physiological activities, such as cell survival, proliferation, differentiation, apoptosis, and metabolism.
  • the dysfunction of protein kinases is closely related to many diseases, including tumors, autoimmune diseases, inflammatory reactions, central nervous system diseases, cardiovascular diseases and diabetes.
  • RET is a proto-oncogene
  • its encoded RET protein is a transmembrane receptor-type tyrosine protein kinase consisting of a cysteine-rich cadherin-like extracellular domain (for ligand binding)
  • the transmembrane region and the intracellular domain with tyrosine kinase activity are composed of three parts.
  • Activated RET proteins can activate multiple downstream signaling pathways, including the RAS/RAF/ERK pathway, PI3K/Akt pathway, and JNK pathway, leading to cell proliferation, migration, and differentiation.
  • RET gene alteration and abnormal expression of wild-type RET gene lead to abnormal activation of RET protein, which makes the signaling pathway overactive, which is one of the main mechanisms of carcinogenesis.
  • Abnormally activated RET proteins participate in the proliferation and invasion of different tumor cells through various signaling pathways, thereby affecting the occurrence and development of tumors.
  • RET gene alterations have a more significant effect on the downstream cascade.
  • RET gene mutations are mainly associated with medullary thyroid cancer and papillary thyroid cancer, and RET gene fusions are mainly associated with non-small cell lung cancer and chronic myeloid leukemia. Therefore, inhibition of RET activity has great medical value (Nature Reviews Cancer, 2014, 14(3): 173-186).
  • RET inhibitors have great potential for the treatment and prevention of various diseases (eg, tumors, irritable bowel syndrome, etc.)
  • tinib also known as Pralsetinib or BLU-667
  • RET resistance mutations such as G810R, G810S, G810C, Y806C, Y806N, and V738A, etc.
  • the present invention provides a compound of formula I, a stereoisomer, tautomer or mixture thereof of said compound, an N-oxide of said compound, a pharmaceutically acceptable salt of said compound , co-crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds in preparation for the treatment or adjunctive treatment of individuals with a RET resistance mutation (e.g. selected from G810R, Use in a medicament for a disease or condition associated with one or more mutations in G810S, G810C, Y806C, Y806N and V738A):
  • a RET resistance mutation e.g. selected from G810R, Use in a medicament for a disease or condition associated with one or more mutations in G810S, G810C, Y806C, Y806N and V738A
  • R 1 is selected from 4-10 membered heterocyclyl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, Halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 ring Alkyl and C 3-6 cycloalkoxy;
  • R 2 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, 4-10-membered heterocyclyl and 5-10-membered heteroaryl, the alkyl, hetero Alkyl, heterocyclyl, and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C1-4alkyl , C1-4haloalkane group, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 cycloalkyl and C 3-6 cycloalkoxy;
  • R 3 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl and C 3-6 cycloalkyl;
  • X 1 , X 2 and X 3 are each independently selected from CH and N.
  • the present invention provides Compound 1, a stereoisomer, tautomer or mixture thereof of said Compound 1, an N-oxide of said Compound 1, a pharmaceutically acceptable compound of said Compound 1 Acceptable salts, co-crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of Compound 1 prepared for use in the treatment or adjunctive treatment of individuals with RET resistance mutations (for example, use in a medicament for a disease or condition associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A), wherein the compound 1 has the following structure:
  • the pharmaceutically acceptable salt of compound 1 is the fumarate salt of compound 1.
  • the present invention provides the compound of formula I, a stereoisomer, tautomer or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable compound of the compound Accepted salts, co-crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds for use in the treatment or adjunctive treatment of individuals with RET resistance mutations (e.g. selected A disease or condition associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A).
  • RET resistance mutations e.g. selected A disease or condition associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A.
  • the invention provides treatment or adjunctive treatment of a disease or condition associated with a RET resistance mutation (eg, one or more mutations selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual A method of A pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound.
  • a RET resistance mutation eg, one or more mutations selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, and V738A
  • the present invention provides the compound of formula I, a stereoisomer, tautomer or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable compound of the compound Accepted salts, co-crystals, polymorphs, or solvates, or stable isotope derivatives, metabolites, or prodrugs of such compounds are prepared for use in modulating (eg, reducing or inhibiting) and RET resistance mutations (eg, selecting). Use in a medicament for aberrant RET activity associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A).
  • the present invention provides the compound of formula I, a stereoisomer, tautomer or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable compound of the compound Accepted salts, co-crystals, polymorphs, or solvates, or stable isotope derivatives, metabolites, or prodrugs of such compounds, for use in modulating (eg, reducing or inhibiting) and RET resistance mutations (eg, selecting).
  • Aberrant RET activity associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A Aberrant RET activity associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A).
  • the invention provides methods for modulating (eg, reducing or inhibiting) abnormalities associated with RET resistance mutations (eg, one or more mutations selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, and V738A).
  • a method of RET activity comprising administering an effective amount of said compound of formula I, a stereoisomer, tautomer or mixture thereof of said compound, an N-oxide of said compound, a pharmacy of said compound an acceptable salt, co-crystal, polymorph or solvate of the above, or a stable isotope derivative, metabolite or prodrug of the compound.
  • the compound has a good inhibitory effect on RET resistance mutation, and has good properties such as pharmacokinetics, safety and the like.
  • Figure 1 In vivo efficacy of compound 1-A and control compounds on the Ba/F3 KIF5B-RET G810R subcutaneous xenograft model.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6, carbon atoms.
  • G 1-6 alkyl and C 1-4 alkyl refer to linear or branched groups having 1-6 carbon atoms and 1-4 carbon atoms, respectively (eg methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), any of which is optionally substituted with one or more (such as 1 to 3) suitable substituents such as halogen (in which case this group is referred to as "haloalkyl”) (eg CH2F , CHF2 , CF3 , CC
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • heteroalkyl refers to an optionally substituted alkyl group having one or more backbone chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof .
  • Numerical ranges may be given (eg C1-6 heteroalkyl) to refer to the number of carbons in the chain, which in this example includes 1-6 carbon atoms.
  • a -CH2OCH2CH3 group is referred to as a C3heteroalkyl .
  • the attachment to the rest of the molecule can be through a heteroatom or a carbon atom in the heteroalkyl chain.
  • haloalkyl refers to an alkyl group substituted with one or more (such as 1 to 3) of the same or different halogen atoms
  • C 1-6 haloalkyl and C 1- 4 "haloalkyl” refers to a haloalkyl having 1 to 6 carbon atoms and 1-4 carbon atoms, respectively, such as -CF3 , -C2F5 , -CHF2 , -CH2F , -CH2CF3 , -CH 2 Cl or -CH 2 CH 2 CF 3 etc.
  • hydroxyalkyl refers to a group formed by replacing a hydrogen atom in an alkyl group with one or more hydroxy groups, such as C1-4 hydroxyalkyl or C1-3 hydroxyalkyl, Examples include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH) CH3 , -C ( CH3 )2OH, and the like.
  • alkoxy means a group in which an oxygen atom is inserted at any reasonable position in an alkyl group (as defined above), eg, C 1-6 alkoxy, C 1-4 alkoxy group or C 1-3 alkoxy group.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy alkoxy, tert-butoxy, pentyloxy, hexyloxy, -CH2 - OCH3 , etc., the alkoxy group is optionally substituted with one or more (such as 1 to 3) the same or different substituents .
  • the term "conjunctive ring” or “fused ring” refers to a ring system formed by two or more ring structures sharing two adjacent atoms with each other.
  • spirocycle refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.
  • bridged ring refers to a ring system formed by two or more ring structures sharing two atoms that are not directly connected to each other.
  • cycloalkyl refers to saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring groups, including but not limited to monocycloalkyl (such as cyclopropyl, cyclobutane) cyclopentyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicycloalkyl groups, including spiro, para (fused) or bridged ring systems (i.e., spirocycloalkyl, para Cyclo(fused ring)alkyl and bridged cycloalkyl, such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, etc.).
  • the cycloalkyl group is optionally substituted with one or more (such as 1 to 3) the same or different substituents.
  • C 3-6 cycloalkyl refers to a cycloalkyl group having 3 to 6 ring carbon atoms, which may be a monocyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo Heptyl or cyclooctyl, or bicycloalkyl, such as C5-8 spirocycloalkyl, C5-8 bridged cycloalkyl, C5-8 fused cycloalkyl, C5-6 spirocycloalkyl , C 5-6 bridged cycloalkyl or C 5-6 fused cycloalkyl.
  • cycloalkoxy means -O-cycloalkyl, wherein cycloalkyl is as defined above.
  • Representative examples of cycloalkoxy include, but are not limited to, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • the term "4-10 membered heterocyclyl” means a heterocyclyl containing 4-10 ring atoms, including but not limited to 4-9 membered heterocyclyl, 4-8 membered heterocyclyl, 4-7-membered heterocyclic group, 5-6-membered heterocyclic group, 3-8-membered heterocyclic group, 3-7-membered heterocyclic group, 4-7-membered nitrogen-containing heterocyclic group, 4-7-membered oxygen-containing heterocyclic group base, 4-7 membered sulfur-containing heterocyclic group, 5-6 membered nitrogen-containing heterocyclic group, 5-6 membered oxygen-containing heterocyclic group, 5-6 membered sulfur-containing heterocyclic group, etc., the "nitrogen-containing heterocyclic group""Oxygen-containingheterocyclyl","oxo-containingheterocyclyl” and "sulfur-containing heterocyclyl” each optionally further contains one or more other heteroatoms selected from oxygen, nitrogen
  • 4-10 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidone (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl.
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and containing at least a bicyclic or polycyclic ring system of a heteroaromatic ring (aromatic ring system containing at least one heteroatom), which may have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, For example 5, 6, 7, 8, 9 or 10 ring atoms.
  • the heteroatom can be oxygen, nitrogen or sulfur.
  • 5-10 membered heteroaryl or "5-10 membered heteroaromatic ring” means a heteroaryl (heteroaryl ring) containing 5 to 10 (eg, 5 to 6) ring atoms ), including 5-10-membered nitrogen-containing heteroaryl, 5-10-membered oxygen-containing heteroaryl, 5-10-membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl Aryl, 5-6 membered sulfur-containing heteroaryl, etc.
  • nitrogen-containing heteroaryl each optionally contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl , thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and 5-10 membered cyclic groups containing these groups.
  • heteroaryl encompasses apical ring structures, and the point of attachment to other groups may be on any ring in the apical ring structure.
  • heteroaryl groups of the present invention also include, but are not limited to, (mono)heteroaryl(mono)heteroaryl, (mono)heteroaryl(mono)aryl, (mono)heteroaryl(mono)aryl ) heterocyclyl and (mono)heteroaryl and (mono)cycloalkyl, such as 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl Arylacyl, 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heterocyclyl or 5-6-membered (mono)heteroaryl-C 4-6 (mono)cycloalkyl, such as 5-6 membered
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (eg, one, two, three, or four) hydrogens on the designated atom are replaced by a selection from the designated group, provided that no more than the designated atom is present in the normal valences in the case and the substitutions form stable compounds. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent can be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be independently and/or together independently Selected optional substituents are substituted. If a nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be independently selected optional substitution of substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent can be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically-labeled compounds that are identical to the compounds of the present invention, except that one or more atoms have the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (eg, deuterium (2H), tritium ( 3H )); isotopes of carbon (eg, 11C , 13C , and14C ) ; isotopes of chlorine (eg 36 Cl); isotopes of fluorine (eg 18 F); isotopes of iodine (eg 123 I and 125 I); isotopes of nitrogen (eg 13 N and 15 N); isotopes of oxygen (eg 15 O) , 17 O and 18 O); isotopes of phosphorus (eg 32 p); and isotopes of sulfur (eg 35 S).
  • isotopes of hydrogen eg, deuterium (2H), tritium ( 3H )
  • isotopes of carbon eg, 11C , 13C , and14C
  • isotopes of chlorine e
  • Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies (eg, assays).
  • the radioisotopes tritium (ie 3 H) and carbon-14 (ie 14 C) are particularly useful for this purpose due to their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes such as11C , 18F , 15O , and13N can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies.
  • Isotopically-labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically-labeled reagent in place of the previously employed non-labeled reagent.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, eg, D2O , acetone-d6, or DMSO - d6.
  • stereoisomer refers to isomers formed due to at least one asymmetric center. In compounds with one or more (eg one, two, three or four) asymmetric centers, it may give rise to rac/meso mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. Certain individual molecules can also exist as geometric isomers (cis/trans). Similarly, the compounds of the present invention may exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. For example, a nitroso-oxime can exist in solution in equilibrium in the following tautomeric forms:
  • Solid line (-), solid wedge can be used in this paper or virtual wedge
  • the chemical bonds of the compounds of the present invention are depicted.
  • the use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, a specific enantiomer, racemic mixture, etc.).
  • the use of real or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomer exists.
  • real and imaginary wedges are used to define relative, rather than absolute, stereochemistry.
  • the compounds of the present invention are intended to be available as stereoisomers (which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • stereoisomers which include cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotational isomers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (eg, racemic mixtures and pairs of diastereomers).
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • Co-crystal refers to the combination of drug active molecules and other physiologically acceptable molecules of acids, bases, salts, and non-ionic compounds in the same crystal lattice by hydrogen bonds, ⁇ - ⁇ stacking, van der Waals forces and other non-covalent bonds. .
  • compositions of the present invention may exist in free form for use in therapy, or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs which are administered to patients in need thereof After administration, the compounds of the invention or their metabolites or residues can be provided directly or indirectly. Accordingly, references herein to "compounds of the present invention" are also intended to encompass the various derivative forms of the compounds described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • acid addition salts for example, hexafluorophosphate, meglumine salt and the like.
  • suitable salts see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” (Wiley-VCH, 2002).
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release free acid or alcohol forms of the present invention) compound).
  • the compounds of the present invention may themselves also be esters.
  • the compounds of the present invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the present invention comprise a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, in particular for example water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides.
  • nitrogen-containing heterocycles capable of forming N-oxides.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include, but are not limited to, use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide , alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperoxybenzoic acid
  • hydrogen peroxide alkyl hydroperoxides
  • alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate sodium perborate
  • dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in the body upon administration of the compounds of the present invention. Such products may result from, for example, oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like, of the administered compound.
  • the present invention includes metabolites of the compounds of the present invention, including compounds prepared by methods of contacting a compound of the present invention with a mammal for a time sufficient to produce the metabolites thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity when administered into or onto the body can be converted into compounds of the invention having the desired activity, for example, by hydrolytic cleavage.
  • prodrugs will be functional derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as “pro-moiety (eg as described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985))" Prepared by substituting appropriate functional groups present in the compounds of the present invention.
  • the present invention also encompasses compounds of the present invention that contain protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecule, thereby forming chemically protected forms of the compounds of the present invention. This can be accomplished with conventional protecting groups, such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • “Pharmaceutically acceptable carrier” refers to a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered and which, within the scope of sound medical judgment, is suitable for contact with humans and/or tissue from other animals without undue toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).
  • the compounds of the present invention or pharmaceutical compositions containing them may act systemically and/or locally. For this purpose, they can be administered by a suitable route.
  • the compounds of the present invention or pharmaceutical compositions comprising the same can be administered in suitable dosage forms.
  • an effective amount refers to the amount of a compound which, when administered, will alleviate to some extent one or more symptoms of the condition being treated.
  • Dosage regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. It is noted that dosage values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosing regimen should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the composition.
  • the amount of the compound of the invention administered will depend on the individual being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. In general, effective doses range from about 0.0001 to about 50 mg per kg body weight per day. In some cases, dose levels not higher than the lower end of the foregoing ranges may be sufficient, while in other cases larger doses may be employed without causing any deleterious side effects, provided that the larger dose is first The dose is divided into several smaller doses to be administered throughout the day.
  • the compound of the present invention may be present in the pharmaceutical composition in an amount or amount of about 0.01 mg to about 1000 mg.
  • treating means reversing, alleviating, inhibiting the progression of the disorder or condition to which such term applies or one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • an “individual” as used herein includes a human or non-human animal.
  • exemplary human subjects include human subjects (referred to as patients) or normal subjects with a disease (eg, a disease described herein).
  • Non-human animals in the present invention include all vertebrates such as non-mammals (eg birds, amphibians, reptiles) and mammals such as non-human primates, livestock and/or domesticated animals (eg sheep, dogs) , cats, cows, pigs, etc.).
  • the compounds of the present invention may be administered in combination with one or more additional therapeutic or prophylactic agents (eg, other drugs used to treat cancer or neoplastic diseases).
  • the methods of the present invention may further comprise administering one or more additional therapeutic or prophylactic agents (eg, other drugs used to treat cancer or neoplastic diseases).
  • the present invention provides a compound of Formula I, a stereoisomer, tautomer or mixture thereof of said compound, an N-oxide of said compound, a pharmaceutically acceptable compound of said compound Salts, co-crystals, polymorphs, or solvates, or stable isotope derivatives, metabolites, or prodrugs of the compounds in preparation for the treatment or adjunctive treatment of individuals with a RET resistance mutation (e.g., selected from G810R , G810S, G810C, Y806C, Y806N and one or more mutations in V738A) in a medicament for a disease or condition associated with:
  • a RET resistance mutation e.g., selected from G810R , G810S, G810C, Y806C, Y806N and one or more mutations in V738A
  • R 1 is selected from 4-10 membered heterocyclyl and 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents independently selected from the group consisting of: hydroxy, Halogen, CN, NO 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 ring Alkyl and C 3-6 cycloalkoxy;
  • R 2 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 heteroalkyl, 4-10-membered heterocyclyl and 5-10-membered heteroaryl, the alkyl, hetero Alkyl, heterocyclyl, and heteroaryl are each optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, CN, NO2, C1-4alkyl , C1-4haloalkane group, C 1-4 hydroxyalkyl, C 1-4 haloalkoxy, C 1-4 heteroalkyl, C 3-6 cycloalkyl and C 3-6 cycloalkoxy;
  • R 3 is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-4 hydroxyalkyl, C 1-4 heteroalkyl and C 3-6 cycloalkyl;
  • X 1 , X 2 and X 3 are each independently selected from CH and N.
  • the compounds of the formula I, the stereoisomers, tautomers or mixtures thereof, the N-oxides of the compounds, the compounds of the formula I, the In a pharmaceutically acceptable salt, co-crystal, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of the compound, the compound of formula I is Compound 1:
  • the pharmaceutically acceptable salt of the compound is the fumarate salt of compound 1.
  • the present invention provides the compound of formula I, a stereoisomer, tautomer or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable compound of the compound Accepted salts, co-crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of said compounds for use in the treatment or adjunctive treatment of individuals with RET resistance mutations (e.g. selected A disease or condition associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A).
  • RET resistance mutations e.g. selected A disease or condition associated with one or more mutations in G810R, G810S, G810C, Y806C, Y806N and V738A.
  • the invention provides treatment or adjunctive treatment of a disease or condition associated with a RET resistance mutation (eg, one or more mutations selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, and V738A) in an individual A method of A pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound.
  • a RET resistance mutation eg, one or more mutations selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, and V738A
  • the disease or condition associated with a RET resistance mutation is a drug-resistant disease, preferably a drug-resistant cancer or tumor or irritable bowel syndrome;
  • the cancer or tumor is, for example, advanced cancer or Tumor or metastatic cancer or tumor;
  • the cancer or tumor is preferably lung cancer (eg non-small cell lung cancer), breast cancer, head and neck cancer, rectal cancer, liver cancer, lymphoma, thyroid cancer (eg medullary thyroid cancer or papillary thyroid cancer) cancer), colon cancer, multiple myeloma, melanoma, glioma, brain tumor or sarcoma.
  • the drug-resistant disease is a disease that is resistant to serpatinib and/or pratinib.
  • the drug-resistant disease is non-small cell lung cancer (eg, RET fusion-positive non-small cell lung cancer), medullary thyroid cancer (such as advanced or metastatic medullary thyroid cancer) or thyroid cancer (eg advanced or metastatic RET fusion positive thyroid cancer).
  • non-small cell lung cancer eg, RET fusion-positive non-small cell lung cancer
  • medullary thyroid cancer such as advanced or metastatic medullary thyroid cancer
  • thyroid cancer eg advanced or metastatic RET fusion positive thyroid cancer
  • the present invention provides the compound of formula I, a stereoisomer, tautomer or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable compound of the compound Acceptable salts, co-crystals, polymorphs, or solvates, or stable isotope derivatives, metabolites, or prodrugs of the compounds are prepared for use in modulating (e.g., reducing or inhibiting) and RET resistance mutations (e.g., Use in a medicament for abnormal RET activity associated with one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A).
  • modulating e.g., reducing or inhibiting
  • RET resistance mutations e.g., Use in a medicament for abnormal RET activity associated with one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A.
  • the present invention provides the compound of formula I, a stereoisomer, tautomer or mixture thereof of the compound, an N-oxide of the compound, a pharmaceutically acceptable compound of the compound Acceptable salts, co-crystals, polymorphs or solvates, or stable isotope derivatives, metabolites or prodrugs of such compounds, for use in modulating (eg reducing or inhibiting) and RET resistance mutations (eg Abnormal RET activity associated with one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A).
  • modulating eg reducing or inhibiting
  • RET resistance mutations eg Abnormal RET activity associated with one or more mutations selected from G810R, G810S, G810C, Y806C, Y806N and V738A.
  • the invention provides methods for modulating (eg, reducing or inhibiting) a RET resistance mutation (eg, one or more mutations selected from the group consisting of G810R, G810S, G810C, Y806C, Y806N, and V738A) associated with RET
  • a method of abnormal RET activity comprising administering an effective amount of said compound of formula I, a stereoisomer, tautomer or mixture thereof of said compound, an N-oxide of said compound, said compound of A pharmaceutically acceptable salt, co-crystal, polymorph or solvate, or a stable isotope derivative, metabolite or prodrug of the compound.
  • the RET resistance mutation is one or more mutations selected from the group consisting of G810R, G810S, and G810C.
  • the RET resistance mutation is selected from one or more of a RET solvent front mutation and a RET hinge mutation.
  • the resistance mutation is a RET solvent front mutation.
  • the RET resistance mutation is an 810 mutation, eg, a G810 mutation.
  • the RET resistance mutation is one or more mutations selected from the group consisting of G810R, G810S and G810C.
  • the compound has the structure of Formula I-A:
  • R 1 , R 2 , R 3 , X 1 and X 2 are as defined above for formula I.
  • the compound has the structure of Formula I-B:
  • R 1 , R 2 , R 3 , X 1 and X 2 are as defined above for formula I.
  • R 1 is a 5-10 membered heteroaryl group optionally formed by one or more independently Substituted with a substituent selected from the group consisting of hydroxy, halogen, CN, C1-4alkyl , C1-4haloalkyl , C3-6cycloalkyl , and C3-6cycloalkoxy .
  • R 1 is a 5-6 membered heteroaryl group, optionally separated by one or more Substituted with a substituent selected from the group consisting of halogen, C 1-3 alkyl and C 3-6 cycloalkyl.
  • R 1 is pyrazolyl, optionally by one or more independently selected from the following Substituent substitution: halogen, C1-3 alkyl (eg methyl) and C3-6 cycloalkyl (eg cyclopropyl).
  • R 1 is methyl-substituted pyrazolyl (eg, 5-methyl-lH-pyrazol-3-yl or 1-methyl-1H-pyrazol-4-yl) or cyclopropyl substituted pyrazolyl (eg 5-cyclopropyl-1H-pyrazol-3-yl).
  • R 2 is selected from halogen (eg Cl), C 1-6 alkyl (eg methyl) and 5-6 membered Heteroaryl, each of said alkyl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4alkyl , C1-4hydroxyalkyl , C1 -4 heteroalkyl, C 3-6 cycloalkyl and C 3-6 cycloalkoxy.
  • halogen eg Cl
  • C 1-6 alkyl eg methyl
  • 5-6 membered Heteroaryl each of said alkyl and heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-4alkyl , C1-4hydroxyalkyl , C1 -4 heteroalkyl, C 3-6 cycloalkyl and C 3-6 cycloalkoxy.
  • R 2 is a 5-6 membered heteroaryl group, optionally separated by one or more Substituted with a substituent selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl and C 3-6 cycloalkoxy.
  • R 2 is a 5-membered heteroaryl group optionally selected by one or more independently selected from the group consisting of The following substituents are substituted: halogen, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 3-6 cycloalkyl and C 3-6 cycloalkoxy.
  • R 2 is pyrrolyl, pyrazolyl, imidazolyl, furanyl, or thiazolyl, optionally substituted by one or Multiple substituents independently selected from the group consisting of F, Cl, methyl, Cyclopropyl and -O-cyclopropyl.
  • R 3 is selected from H, C 1-6 alkyl and C 3-6 cycloalkyl.
  • R3 is selected from H and C1-6 alkyl.
  • R3 is H or methyl
  • X 1 is CH or N; preferably, X 1 is N.
  • X 2 is CH or N; preferably, X 2 is CH.
  • X 3 is CH or N; preferably, X 3 is N.
  • the present invention encompasses any combination of the above embodiments.
  • the compounds include, but are not limited to:
  • the compound is:
  • the pharmaceutically acceptable salt is a fumarate salt.
  • the pharmaceutically acceptable salt of the compound is:
  • the compounds of the present invention can be prepared by the methods described in WO 2020/168939 A1.
  • the compounds of the present invention are isolated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and/or flash column chromatography (Flash column chromatography), and their structures are confirmed by 1 H NMR and/or MS. Reaction monitoring was performed by TLC or LC-MS.
  • TLC used silica gel GF 254 as the stationary phase.
  • Flash column chromatography uses a Biotage flash column chromatograph.
  • Prep-HPLC used Agilent Model 1260, Waters Model 2489 and GeLai Model 3500 chromatographs.
  • Microwave reactions were performed using a BiotageInitiator microwave reactor.
  • reaction temperature is room temperature (15-30°C).
  • the reagents used in this application were purchased from companies such as Acros Organics, Aldrich Chemical Company, or Tuber Chemicals.
  • the sixth step 2-(6-(6-((6-(4-chloro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]Heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 9)
  • the first step 1-(4-(1,3-dioxolane-2-yl)phenyl)-3-cyclopropyl-1H-pyrazole (14c) and 1-(4-(1 , 3-dioxolane-2-yl)phenyl)-5-cyclopropyl-1H-pyrazole (14d)
  • Step 2 4-(5-Cyclopropyl-1H-pyrazol-1-yl)benzaldehyde (14e) and 4-(3-cyclopropyl-1H-pyrazol-1-yl)benzaldehyde (14f) )
  • Example 4 2-(6-(6-((6-(4-Fluoro-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-diazabicyclo[3.1 .1]
  • the fumarate salt of heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine ( Compound 1-A)
  • the fourth step 2-(6-(6-((6-(3-fluoro-5-methyl-1H-pyrazol-1-yl)pyridin-3-yl)methyl)-3,6-di azabicyclo[3.1.1]heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine ( Compound 28)
  • Example 8 2-(4-Fluoro-1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine -2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl ) fumarate salt of propan-2-ol (compound 30-A)
  • Step 5 6-(4-Fluoro-3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)nicotinaldehyde (30f)
  • Step 6 2-(4-Fluoro-1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine -2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl ) propan-2-ol (compound 30)
  • Step 7 2-(4-Fluoro-1-(5-((3-(5-(4-methyl-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidine -2-yl)pyridin-2-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl)methyl)pyridin-2-yl)-1H-pyrazol-3-yl ) fumarate salt of propan-2-ol (compound 30-A)
  • the first step 2-(6-(6-((5-chloropyrazin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyridine- 3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (31b)
  • the second step 2-(6-(6-((5-(4-Fluoro-1H-pyrazol-1-yl)pyrazin-2-yl)methyl)-3,6-diazabicyclo[ 3.1.1] Heptan-3-yl)pyridin-3-yl)-6-methyl-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Compound 31)
  • RET-G810R, RET-G810S and RET-G810C drug-resistant mutant RET enzymes
  • the three drug-resistant mutant RET enzymes were respectively mixed with different concentrations of test compounds (in the compound inhibition rate test: for RET-G810R and RET-G810C, the compound concentrations were 300 and 1000 nM; for RET-G810S, the compound concentrations were 30 and 300 nM.
  • Percentage of relative inhibitory activity 1-(compound groups of different concentrations-blank control)/(negative control-blank control)*100%
  • the percent relative inhibitory activity of the compounds at different concentrations was plotted against the compound concentration, the curve was fitted according to a four-parameter model, and the IC50 value was calculated by the following formula:
  • y is the percentage of relative inhibitory activity
  • max and min are the maximum and minimum values of the fitted curve, respectively
  • x is the logarithmic concentration of the compound
  • Hillslope is the slope of the curve.
  • Inhibition rate % [1-(mean value of detection signal of compound group-mean value of blank control signal)/(mean value of negative control signal-mean value of blank control signal)]*100%; using "log(agonist)” in GraphPad Prism 6.0 vs response-variable slope (four parameters)” four-parameter equation was fitted to the inhibition rate %, and IC 50 was calculated.
  • OBJECTIVE To study the in vivo efficacy of the compounds in the Ba/F3 KIF5B-RET G810R subcutaneous tumor-bearing BALB/c Nude mouse model.
  • Drug preparation Compound 1-A, BLU-667, Loxo-292 were prepared into a homogeneous suspension solution with 0.5% methyl cellulose (MC) as a solvent for PO (gavage) and BID administration.
  • MC methyl cellulose
  • Table 9 and Figure 1 The results are shown in Table 9 and Figure 1.
  • Statistical analysis was performed using PrismGraphpad 8.0 software based on relative tumor volume at the end of the trial. Two-way ANOVA was used for comparison between two groups and multiple groups, and p ⁇ 0.05 was considered to have significant difference.
  • the tumor growth inhibition rates (TGI (%)) of compound 1-A and control compounds BLU-667 and Loxo-292 were 72.37% and 29.78%, respectively. and 2.69%, indicating that the tumor inhibitory effect of compound 1-A is better than that of control compounds BLU-667 and Loxo-292, and both p ⁇ 0.05 compared with control compounds BLU-667 and Loxo-292.
  • VP -1 tumor volume on the 1st day before administration
  • VP12 tumor volume on the 12th day of administration.

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JP2023535361A (ja) * 2020-07-28 2023-08-17 スーチュアン・コールン－バイオテック・バイオファーマシューティカル・カンパニー・リミテッド ピリミジン系化合物の塩、結晶形およびその調製方法
JP7688690B2 (ja) 2020-07-28 2025-06-04 スーチュアン・コールン－バイオテック・バイオファーマシューティカル・カンパニー・リミテッド ピリミジン系化合物の塩、結晶形およびその調製方法
WO2024240017A1 (zh) 2023-05-19 2024-11-28 四川科伦博泰生物医药股份有限公司 杂环化合物治疗与ret基因改变相关疾病的用途和方法
WO2026017002A1 (zh) * 2024-07-16 2026-01-22 四川科伦博泰生物医药股份有限公司 以杂环化合物为活性成分的药物组合物、其制备方法及用途
WO2026018023A1 (en) 2024-07-19 2026-01-22 Ellipses Pharma Ltd Synergistic combinations comprising lunbotinib for anti-cancer therapy

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