WO2020257189A1 - Macrocycles pour le traitement d'une maladie - Google Patents

Macrocycles pour le traitement d'une maladie Download PDF

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WO2020257189A1
WO2020257189A1 PCT/US2020/037917 US2020037917W WO2020257189A1 WO 2020257189 A1 WO2020257189 A1 WO 2020257189A1 US 2020037917 W US2020037917 W US 2020037917W WO 2020257189 A1 WO2020257189 A1 WO 2020257189A1
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Prior art keywords
alkyl
compound
pharmaceutically acceptable
acceptable salt
deuterium
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PCT/US2020/037917
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English (en)
Inventor
Jingrong Jean Cui
Evan W. ROGERS
Dayong Zhai
Jane Ung
Vivian NGUYEN
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Turning Point Therapeutics, Inc.
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Publication of WO2020257189A1 publication Critical patent/WO2020257189A1/fr

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D498/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18Bridged systems

Definitions

  • the present disclosure relates to certain macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat disease, such as cancer.
  • RET is a receptor tyrosine kinase that was initially discovered in 1985 through transfection of NIH3T3 cells with human lymphoma DNA
  • RET is expressed with its highest levels in early embryogenesis (during which it has diverse roles in different tissues) and decreases to relatively low levels in normal adult tissues (Pachnis, V., et al. Development 1993, 119, 1005-1017). RET plays a critical role in the development of enteric nervous system and kidneys during embryogenesis (Schuchardt, A. et al. Nature 1994, 367:380-383). RET activation regulates the downstream signalling pathways (RAS/MAPK/ERK, PI3K/AKT, and JAK-STAT etc.), leading to cellular proliferation, migration, and differentiation (Mulligan, LM. Nat Rev Cancer. 2014, 14(3): 173-86).
  • Gain-of-function mutations of RET with constitutive activation have been found in heritable and sporadic tumors including activating point mutations within the full-length RET protein or genomic rearrangements that produce chimeric RET oncoproteins in the cytosol.
  • the heritable oncogenic RET mutations are found in multiple endocrine neoplasia type 2 (MEN2) including medullary thyroid cancer (MTC) and familial MTC with more than 80 pathogenic variants spanning RET exons 5-16 reported (Mulligan, LM. Nat Rev Cancer. 2014, 14(3): 173- 86).
  • RET M918T and RET A883F are found in 40-65% of sporadic MTC.
  • RET fusion oncoproteins have been identified in sporadic tumors.
  • the RET rearrangements are originally reported in papillary thyroid cancers (PTCs) (Grieco, M. et al. Cell. 1990, 23; 60 (4):557-63.).
  • PTCs papillary thyroid cancers
  • the resulting fusion transcripts composed of the 3’ end of RET kinase domain and the 5’ end of separate partner genes (CCDC6, NCOA4, TRIM24, TRIM33, PRKAR1A, GOLGA5, KTN1, ERC1, MBD1, and TRIM27 etc.).
  • RET fusions are identified in approximately 20% 40% of PTCs, and CCDC6-RET and NCOA4-RET are the most commonly identified RET fusions in PTCs (Drilon A, et al. Nat Rev Clin Oncol. 2017 Nov 14. doi: 10.1038/nrclinonc.2017.175). RET gene fusions are also found in approximately l%-2% of non-small cell lung cancer (NSCLC) (Gainor JF, Shaw AT. Oncologist. 2013, 18(7):865-75), and over 50% of RET fusions in NSCLC is KIF5B-RET, representing the most frequent RET fusion form.
  • NSCLC non-small cell lung cancer
  • the RET inhibitors have relatively low response rates and short treatment duration in the treatment of NSCLC patients with KIF5B-RET fusion gene in multiple clinical trials (Drilon, A. Nat Rev Clin Oncol. 2017 Nov 14. doi: 10.1038/nrclinonc. 2017.175). It was reported that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB -vesicle-dependent RET-SRC-EGFR-FGFR signaling hub (Das TK and Cagan RL Cell Rep. 2017, 20(10):2368-2383).
  • SRC kinase The inhibition of SRC kinase will have the potential to stop the recruitment of multiple RTKs via the N terminus of the KIF5B-RET fusion protein and the oncogenic signaling to increase the therapeutic efficiency of RET inhibitors.
  • Src family tyrosine kinases regulate MTC cellular proliferation in vitro and mediate growth signals by increasing DNA synthesis and decreasing apoptosis (Liu Z, et al. J. Clin. Endocrinol. Metab. 2004, 89, 3503-3509). Therefore, a dual inhibitor of RET and SRC represents a highly desired therapeutic intervention to maximally target abnormal RET signaling in cancers.
  • Endochondral ossification is a process that results in both the replacement of the embryonic cartilaginous skeleton during organogenesis and the growth of long bones until adult height is achieved.
  • Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling plays a vital role in the development and maintenance of growth plates in endochondral ossification process
  • FGFR1 in chondrocytes causes joint fusion. Deletion of both FGFR1 and FGFR2 in mice caused a decreased length of the growth plate with a reduced number of proliferating chondrocytes (Karuppaiah K 2016). Therefore, the selectivity over FGFRs is an important parameter for better safety profile, especially for pediatric population.
  • the disclosure relates to a compound of the formula I
  • each R 1 and R 2 is independently H, deuterium, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, mono- or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS
  • heterocycloalkyl C 6 -Cio aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -OR e , -OC(O)R e ,
  • R 6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -OR e , -SR e , or -NR e R f ;
  • each R 7 is independently hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl; [015] m is 1 or 2; and
  • n is i, 2, or 3;
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula II
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula III
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula IV
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula V
  • the disclosure relates to a compound or a pharmaceutically acceptable salt thereof, having the formula VI
  • each R 1 and R 2 is independently H, deuterium, halogen, Ci- , alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -Cio aryl, mono- or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b , -OS(O)R a , -OS(O) 2 R a , -SR a , -S(O)R a , -S(O) 2 R a , -S(O)NR a R b , -S(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS(O) 2 NR a R b , -OS(
  • heterocycloalkyl C 6 -Cio aryl, and mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C1-C6 alkyl, Ci-Ce haloalkyl, -OR e , -OC(O)R e ,
  • each R 3 is independently H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in
  • R 6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -OR e , -SR e , or -NR e R f ;
  • each R 7 is independently hydrogen or deuterium
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C ⁇ -Ce alkyl, Ci-Ce alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, and 5- to 7- membered heteroaryl;
  • m is 1 or 2;
  • n is i, 2, or 3;
  • [066] 26 A pharmaceutical composition comprising a compound of any one of the preceding clauses, or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.
  • 27 A method of treating cancer comprising administering to a subject in need of such treatment an effective amount of at least one compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof.
  • a method of inhibiting RET or SRC comprising contacting a cell comprising one or more of such kinases with an effective amount of at least one compound of any one of clauses 1 to 25, or a pharmaceutically acceptable salt thereof, and/or with at least one pharmaceutical composition of the disclosure, wherein the contacting is in vitro, ex vivo, or in vivo.
  • yield refers to a mass of the entity for which the yield is given with respect to the maximum amount of the same entity that could be obtained under the particular stoichiometric conditions. Concentrations that are given as percentages refer to mass ratios, unless indicated differently.
  • alkyl includes a chain of carbon atoms, which is optionally branched and contains from 1 to 20 carbon atoms. It is to be further understood that in certain embodiments, alkyl may be advantageously of limited length, including C1-C12, C1-C10, C1-C 9 , C 1 -C 8 , C 1 -C 7 , C 1 -C 6 , and C 1 -C 4 , Illustratively, such particularly limited length alkyl groups, including Ci-Cs, Ci-C 7 , Ci-C 6 , and C 1 -C 4 , and the like may be referred to as“lower alkyl.” Illustrative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-p
  • Alkyl may be substituted or unsubstituted.
  • “alkyl” may be combined with other groups, such as those provided above, to form a functionalized alkyl.
  • the combination of an“alkyl” group, as described herein, with a “carboxy” group may be referred to as a“carboxyalkyl” group.
  • Other non-limiting examples include hydroxyalkyl, aminoalkyl, and the like.
  • Alkenyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3-butenyl, and the like.
  • alkynyl includes a chain of carbon atoms, which is optionally branched, and contains from 2 to 20 carbon atoms, and also includes at least one carbon-carbon triple bond (i.e., CoC). It will be understood that in certain embodiments, alkynyl may each be advantageously of limited length, including C 2 -C 12 , C 2 -C 9 , C 2 -C 8 , C 2 -C 7 , C 2 -C 6 , and C 2 -C 4 .
  • alkynyl groups including C 2 -C 8 , C 2 -C 7 , C 2 -O,, and C 2 -C 4 may be referred to as lower alkynyl.
  • Alkynyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl, and the like.
  • the term“aryl” refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system.
  • aryl may be advantageously of limited size such as C6-C10 aryl.
  • Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl and anthracenyl. The aryl group may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • cycloalkyl refers to a 3 to 15 member all-carbon monocyclic ring, including an all-carbon 5-member/6-member or 6-member/6-member fused bicyclic ring, or a multicyclic fused ring (a“fused” ring system means that each ring in the system shares an adjacent pair of carbon atoms with each other ring in the system) group, or a carbocyclic ring that is fused to another group such as a heterocyclic, such as ring 5- or 6-membered cycloalkyl fused to a 5- to 7- membered heterocyclic ring, where one or more of the rings may contain one or more double bonds but the cycloalkyl does not contain a completely conjugated pi-electron system.
  • cycloalkyl may be advantageously of limited size such as C3-C13, C3-C9, C3-C6 and C4-C6.
  • Cycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, norbornyl, norbornenyl, 9//-lluoren-9-yl, and the like.
  • Illustrative examples of cycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties: . a . O . 0 . 0. 0 . o . 0 . 0 . 0 0 0
  • heterocycloalkyl refers to a monocyclic or fused ring group having in the ring(s) from 3 to 12 ring atoms, in which at least one ring atom is a heteroatom, such as nitrogen, oxygen or sulfur, the remaining ring atoms being carbon atoms.
  • Heterocycloalkyl may optionally contain 1, 2, 3 or 4 heteroatoms.
  • a heterocycloalkyl group may be fused to another group such as another heterocycloalkyl, or a heteroaryl group.
  • heterocycloalkyl may be advantageously of limited size such as 3- to 7-membered heterocycloalkyl, 5- to 7-membered heterocycloalkyl, 3-, 4-, 5- or 6-membered heterocycloalkyl, and the like.
  • Heterocycloalkyl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • Illustrative heterocycloalkyl groups include, but are not limited to, oxiranyl, thianaryl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4- dioxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, oxepanyl, 3,4-dihydro-2H-pyranyl, 5,6-dihydro-2H-pyranyl, 2H-pyranyl, 1, 2, 3, 4-tetrahydropyridinyl, and the like.
  • Illustrative examples of heterocycloalkyl groups shown in graphical representations include the following entities, in the form of properly bonded moieties:
  • heteroaryl refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that in certain embodiments, heteroaryl may be advantageously of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like.
  • Illustrative examples of heteroaryl groups shown in graphical representations include the following entities, in the form of properly bonded
  • “hydroxy” or“hydroxyl” refers to an -OH group.
  • alkoxy refers to both an -O-(alkyl) or an -O- (unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • aryloxy refers to an -O-aryl or an -O-heteroaryl group. Representative examples include, but are not limited to, phenoxy, pyridinyloxy, furanyloxy, thienyloxy, pyrimidinyloxy, pyrazinyloxy, and the like, and the like.
  • mercapto refers to an -SH group.
  • alkylthio refers to an -S-(alkyl) or an -S-(unsubstituted cycloalkyl) group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, and the like.
  • arylthio refers to an -S-aryl or an -S-heteroaryl group. Representative examples include, but are not limited to, phenylthio, pyridinylthio, furanylthio, thienylthio, pyrimidinylthio, and the like.
  • halo or“halogen” refers to fluorine, chlorine, bromine or iodine.
  • cyano refers to a -CN group.
  • oxo represents a carbonyl oxygen.
  • a cyclopentyl substituted with oxo is cyclopentanone.
  • substituted means that the specified group or moiety bears one or more substituents.
  • unsubstituted means that the specified group bears no substituents.
  • substitution is meant to occur at any valency-allowed position on the system.
  • “substituted” means that the specified group or moiety bears one, two, or three substituents.
  • “substituted” means that the specified group or moiety bears one or two substituents.
  • “substituted” means the specified group or moiety bears one substituent.
  • “optional” or“optionally” means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “wherein each hydrogen atom in C ⁇ -Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3-to 7- membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bicyclic heteroaryl is independently optionally substituted by C 1 -C 6 alkyl” means that an alkyl may be but need not be present on any of the C 1 -C 6 alkyl, CF-Ce alkenyl, C 2 -O, alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bicyclic heteroaryl by replacement of
  • “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances.
  • the use of“independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different.
  • the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
  • the phrase“R 8 and R 9 combine to form a C 3 -C 7 cycloalkyl, a 5- to 8- membered heterocycloalkyl, C6-C10 aryl, or 5- to 7-membered heteroaryl” also means that R 8 and R 9 are taken together with the carbon atoms to which they are attached to form a a C 3 -C 7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C 6 -Cio aryl, or 5- to 7-membered heteroaryl.
  • “R 8 and R 9 combine to form a C 3 -C 7 cycloalkyl” used in connection with the embodiments described herein includes fragments represented by the following:
  • the term“pharmaceutically acceptable salt” refers to those salts which counter ions which may be used in pharmaceuticals. See, generally, S.M. Berge, et ak, “Pharmaceutical Salts,” J. Pharm. Sci., 1977, 66, 1-19.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of subjects without undue toxicity, irritation, or allergic response.
  • a compound described herein may possess a sufficiently acidic group, a sufficiently basic group, both types of functional groups, or more than one of each type, and accordingly react with a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Such salts include:
  • acid addition salts which can be obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid,
  • inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, and perchloric acid and the like
  • organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methane sulfonic acid
  • ethanesulfonic acid p-toluenesulfonic acid
  • salicylic acid tartaric acid, citric acid, succinic acid or malonic acid and the like
  • a metal ion e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion
  • organic base such as ethanolamine, diethanolamine, triethanolamine, trimethamine, N-methylglucamine, and the like.
  • Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen-phosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne- 1,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
  • a pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as man
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulf
  • the disclosure also relates to pharmaceutically acceptable prodrugs of the compounds of
  • prodrug means a precursor of a designated compound that, following administration to a subject, yields the compound in vivo via a chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug on being brought to physiological pH is converted to the compound of Formula I, II, III, IV, V, or VI).
  • A“pharmaceutically acceptable prodrug” is a prodrug that is non- toxic, biologically tolerable, and otherwise biologically suitable for administration to the subject. Illustrative procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in“Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
  • the present disclosure also relates to pharmaceutically active metabolites of compounds of Formula I, II, III, IV, V, or VI, and uses of such metabolites in the methods of the disclosure.
  • A“pharmaceutically active metabolite” means a pharmacologically active product of metabolism in the body of a compound of Formula I, II, III, IV, V, or VI, or salt thereof.
  • Prodrugs and active metabolites of a compound may be determined using routine techniques known or available in the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).
  • any formula depicted herein is intended to represent a compound of that structural formula as well as certain variations or forms.
  • a formula given herein is intended to include a racemic form, or one or more enantiomeric, diastereomeric, or geometric isomers, or a mixture thereof.
  • any formula given herein is intended to refer also to a hydrate, solvate, or polymorph of such a compound, or a mixture thereof.
  • compounds depicted by a structural formula containing the symbol“ n/nl - G ” include both stereoisomers for the carbon atom to which the symbol“ iLLL '” is attached, specifically both the bonds“ ” and . 111 111” are encompassed by the meaning of“/vw p or example, in some exemplary embodiments, certain compounds provided herein can be described by the formula
  • any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, n C, 13 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, 35 S, 18 F, 36 C1, and 125 I, respectively.
  • Such isotopically labelled compounds are useful in metabolic studies (preferably with 14 C), reaction kinetic studies (with, for example 2 H or 3 H), detection or imaging techniques [such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)] including drug or substrate tissue distribution assays, or in radioactive treatment of patients.
  • detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT)
  • PET positron emission tomography
  • SPECT single-photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
  • any disubstituent referred to herein is meant to encompass the various attachment possibilities when more than one of such possibilities are allowed.
  • compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula wherein Y is otherwise defined as described herein. In still other embodiments, compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula
  • compounds described herein comprise a moiety of the formula In still other embodiments, compounds described herein comprise a moiety of the formula
  • each R 1 and R 2 is independently H, deuterium, halogen, C 1 -C 6 , alkyl, C 2 -C 6 alkenyl, Ci-Ce alkynyl, C3-C6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C6-C10 aryl, mono- or bicyclic heteroaryl, -OR a , -OC(O)R a , -OC(O)R a , -OC(O)NR a R b ,
  • R 1 is H or D.
  • R 2 is H or deuterium.
  • each R 3 when present, is H or C1-C6 alkyl.
  • R 4 is H or deuterium.
  • R 5 is F.
  • R 6 is H, deuterium, or C1-C6 alkyl, wherein each hydrogen atom in C1-C6 alkyl is independently optionally substituted by deuterium, halogen, -OR e , -SR e , or -NR e R f . In some embodiments R 6 is H.
  • each R 7 is independently hydrogen or deuterium. In some embodiments, R 7 is H.
  • R 8 and R 9 together with the carbons which they are attached combine to form a C3-C7 cycloalkyl, a 5- to 8-membered heterocycloalkyl, C6-C10 aryl, or 5- to
  • R 8 and R 9 combine to form a cyclobutane ring, cyclopentane ring, or
  • R 8 and R 9 combine to form a 3-, 4-, 5- or 6-membered heterocycloalkyl, wherein each hydrogen atom in the 3-, 4-, 5- or 6-membered heterocycloalkyl is independently optionally substituted by deuterium, halogen, -OH, -CN, -OC1-C6 alkyl, -NH 2 ,
  • Ci-C 6 alkyl -NH(Ci-Ce alkyl), -N(Ci-Ce alkyl) 2 , -NHC(O)Ci-C 6 alkyl, -N(CI-C 6 alkyl)C(O)Ci-C 6 alkyl, -NHC(O)NH 2 , -NHC(O)NH(Ci-C 6 alkyl), -N(CI-C 6 alkyl)C(O)NH 2 ,
  • each R a , R b , R c , R d , R e , and R f is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 2 -Ce alkenyl, C 2 -Ce alkynyl, C 3 -C 6 cycloalkyl,
  • n is 1 or 2. In some embodiments, m is 1.
  • n is 1, 2, or 3. In some embodiments, n is 1 or 2.
  • compositions comprising the compounds described herein may further comprise one or more pharmaceutically-acceptable excipients.
  • a pharmaceutically-acceptable excipient is a substance that is non-toxic and otherwise biologically suitable for administration to a subject. Such excipients facilitate administration of the compounds described herein and are compatible with the active ingredient. Examples of pharmaceutically-acceptable excipients include stabilizers, lubricants, surfactants, diluents, anti oxidants, binders, coloring agents, bulking agents, emulsifiers, or taste-modifying agents.
  • pharmaceutical compositions according to the invention are sterile compositions. Pharmaceutical compositions may be prepared using compounding techniques known or that become available to those skilled in the art.
  • compositions are also contemplated by the invention, including compositions that are in accord with national and local regulations governing such compositions.
  • compositions and compounds described herein may be formulated as solutions, emulsions, suspensions, or dispersions in suitable pharmaceutical solvents or carriers, or as pills, tablets, lozenges, suppositories, sachets, dragees, granules, powders, powders for reconstitution, or capsules along with solid carriers according to conventional methods known in the art for preparation of various dosage forms.
  • Pharmaceutical compositions of the invention may be administered by a suitable route of delivery, such as oral, parenteral, rectal, nasal, topical, or ocular routes, or by inhalation.
  • the compositions are formulated for intravenous or oral administration.
  • the compounds the invention may be provided in a solid form, such as a tablet or capsule, or as a solution, emulsion, or suspension.
  • the compounds of the invention may be formulated to yield a dosage of, e.g., from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • Oral tablets may include the active ingredient(s) mixed with compatible pharmaceutically acceptable excipients such as diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and preservative agents.
  • Suitable inert fillers include sodium and calcium carbonate, sodium and calcium phosphate, lactose, starch, sugar, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol, and the like.
  • Exemplary liquid oral excipients include ethanol, glycerol, water, and the like.
  • Starch polyvinyl -pyrrolidone (PVP), sodium starch glycolate,
  • microcrystalline cellulose, and alginic acid are exemplary disintegrating agents.
  • Binding agents may include starch and gelatin.
  • the lubricating agent if present, may be magnesium stearate, stearic acid, or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract, or may be coated with an enteric coating.
  • Capsules for oral administration include hard and soft gelatin capsules.
  • active ingredient(s) may be mixed with a solid, semi-solid, or liquid diluent.
  • Soft gelatin capsules may be prepared by mixing the active ingredient with water, an oil, such as peanut oil or olive oil, liquid paraffin, a mixture of mono and di-glycerides of short chain fatty acids, polyethylene glycol 400, or propylene glycol.
  • Liquids for oral administration may be in the form of suspensions, solutions, emulsions, or syrups, or may be lyophilized or presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may optionally contain:
  • suspending agents for example, sorbitol, methyl cellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel and the like
  • non-aqueous vehicles e.g., oil (for example, almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol, or water
  • preservatives for example, methyl or propyl p-hydroxybenzoate or sorbic acid
  • wetting agents such as lecithin; and, if desired, flavoring or coloring agents.
  • the agents of the invention may be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity or in parenterally acceptable oil.
  • Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
  • Such forms may be presented in unit-dose form such as ampoules or disposable injection devices, in multi dose forms such as vials from which the appropriate dose may be withdrawn, or in a solid form or pre-concentrate that can be used to prepare an injectable formulation.
  • Illustrative infusion doses range from about 1 to 1000 pg/kg/minute of agent admixed with a pharmaceutical carrier over a period ranging from several minutes to several days.
  • inventive pharmaceutical compositions may be administered using, for example, a spray formulation also containing a suitable carrier.
  • inventive compositions may be formulated for rectal administration as a suppository.
  • the compounds of the present invention are preferably formulated as creams or ointments or a similar vehicle suitable for topical administration ⁇
  • the inventive compounds may be mixed with a pharmaceutical carrier at a concentration of about 0.1% to about 10% of drug to vehicle.
  • Another mode of administering the agents of the invention may utilize a patch formulation to effect transdermal delivery.
  • “treat” or“treatment” encompass both“preventative” and “curative” treatment.“Preventative” treatment is meant to indicate a postponement of development of a disease, a symptom of a disease, or medical condition, suppressing symptoms that may appear, or reducing the risk of developing or recurrence of a disease or symptom. “Curative” treatment includes reducing the severity of or suppressing the worsening of an existing disease, symptom, or condition.
  • treatment includes ameliorating or preventing the worsening of existing disease symptoms, preventing additional symptoms from occurring, ameliorating or preventing the underlying systemic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, relieving the disorder or disease, causing regression of the disorder or disease, relieving a condition caused by the disease or disorder, or stopping the symptoms of the disease or disorder.
  • subject refers to a mammalian patient in need of such treatment, such as a human.
  • Exemplary diseases include cancer, pain, neurological diseases, autoimmune diseases, and inflammation.
  • Cancer includes, for example, lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.
  • Pain includes, for example, pain from any source or etiology, including cancer pain, pain from chemotherapeutic treatment, nerve pain, pain from injury, or other sources.
  • Autoimmune diseases include, for example, rheumatoid arthritis, Sjogren syndrome, Type I diabetes, and lupus.
  • Exemplary neurological diseases include Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic lateral sclerosis, and Huntington’s disease.
  • Exemplary inflammatory diseases include atherosclerosis, allergy, and inflammation from infection or injury.
  • the compounds and pharmaceutical compositions of the invention specifically target receptor tyrosine kinases, in particular RET.
  • the compounds and pharmaceutical compositions of the invention specifically target non-receptor tyrosine kinases, in particular SRC.
  • the compounds and pharmaceutical compositions of the invention specifically target receptor tyrosine kinases and non-receptor tyrosine kinases, such as RET and SRC, respectively.
  • compositions can be used to prevent, reverse, slow, or inhibit the activity of one or more of these kinases.
  • methods of treatment target cancer In preferred embodiments, methods are for treating lung cancer or non-small cell lung cancer.
  • an“effective amount” means an amount sufficient to inhibit the target protein. Measuring such target modulation may be performed by routine analytical methods such as those described below. Such modulation is useful in a variety of settings, including in vitro assays.
  • the cell is preferably a cancer cell with abnormal signaling due to upregulation of RET and/or SRC.
  • an“effective amount” means an amount or dose sufficient to generally bring about the desired therapeutic benefit in subjects needing such treatment.
  • Effective amounts or doses of the compounds of the invention may be ascertained by routine methods, such as modeling, dose escalation, or clinical trials, taking into account routine factors, e.g., the mode or route of administration or drug delivery, the pharmacokinetics of the agent, the severity and course of the infection, the subject’s health status, condition, and weight, and the judgment of the treating physician.
  • An exemplary dose is in the range of about from about 0.1 mg to 1 g daily, or about 1 mg to 50 mg daily, or about 50 to 250 mg daily, or about 250 mg to 1 g daily.
  • the total dosage may be given in single or divided dosage units (e.g., BID, TID, QID).
  • the dose may be adjusted for preventative or maintenance treatment.
  • the dosage or the frequency of administration, or both may be reduced as a function of the symptoms, to a level at which the desired therapeutic or prophylactic effect is maintained.
  • treatment may cease.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms. Patients may also require chronic treatment on a long-term basis.
  • inventive compounds described herein may be used in pharmaceutical compositions or methods in combination with one or more additional active ingredients in the treatment of the diseases and disorders described herein.
  • Further additional active ingredients include other therapeutics or agents that mitigate adverse effects of therapies for the intended disease targets. Such combinations may serve to increase efficacy, ameliorate other disease symptoms, decrease one or more side effects, or decrease the required dose of an inventive compound.
  • the additional active ingredients may be administered in a separate pharmaceutical composition from a compound of the present invention or may be included with a compound of the present invention in a single pharmaceutical composition.
  • the additional active ingredients may be administered simultaneously with, prior to, or after administration of a compound of the present invention.
  • Combination agents include additional active ingredients are those that are known or discovered to be effective in treating the diseases and disorders described herein, including those active against another target associated with the disease.
  • compositions and formulations of the invention, as well as methods of treatment can further comprise other drugs or pharmaceuticals, e.g., other active agents useful for treating or palliative for the target diseases or related symptoms or conditions.
  • additional such agents include, but are not limited to, kinase inhibitors, such as EGFR inhibitors (e.g., erlotinib, gefitinib), Raf inhibitors (e.g., vemurafenib), VEGFR inhibitors (e.g., sunitinib), ALK inhibitors (e.g., crizotinib) standard chemotherapy agents such as alkylating agents, antimetabolites, anti-tumor antibiotics, topoisomerase inhibitors, platinum drugs, mitotic inhibitors, antibodies, hormone therapies, or corticosteroids.
  • suitable combination agents include anti-inflammatories such as NSAIDs.
  • the pharmaceutical compositions of the invention may additionally comprise one or more of such active agents, and methods of treatment may additionally comprise administering an effective amount of one or more of such active agents.
  • Step 3 To a solution of A-4 (865 mg, 3.11 mmol, 1.0 eq.) in ethanol (16.0 mL), THF (6.00 mL) and water (11.0 mL) was added zinc powder (1.02 g, 15.6 mmol, 5.0 eq.) and ammonium chloride (700 mg, 13.1 mmol, 4.21 eq.) at 0 °C. The mixture was stirred at 0 °C for 0.5 hr. The mixture was filtered and the filtrate was dilute with water (50.0 mL).
  • Step 4 To a solution of (15,2 ⁇ )-2-aminocyclopentanol (262 mg, 1.90 mmol, 1.00 eq. HC1, available from e.g.
  • Step 5 To a solution of A-6 (520 mg, 1.69 mmol, 1.00 eq.) in DML (8.00 mL) was added cesium carbonate (1.66 g, 5.11 mmol, 3.03 eq.). The mixture was stirred at 130 °C for 5 hrs. The mixture was quenched by water (20.0 mL) and extracted with ethyl acetate (20.0 mL x 3). The organic layer was washed by brine (50.0 mL) and dried over anhydrous sodium. The residue was purified by Prep-HPLC to give A (100 mg, 336 pmol, 20 % yield, 97.1% purity) as a yellow solid.
  • Step 1 To a solution of 1-1 (374.47 mg, 2 mmol, tert-butyl ((lr,3r)-3- hydroxycyclobutyl)carbamate, available from e.g. Enamine Ltd.), 1-2 (408.33 mg, 2.40 mmol, methyl 5-fluoro-2-hydroxybenzoate, available from e.g. Sigma- Aldrich), and PPI13 (786.86 mg, 3.00 mmol) in anhydrous DCM (2.23 mL) at 0 °C was added DIAD (647.07 mg, 3.20 mmol, 628.22 pL) with stirring. The mixture was stirred for 3 hr as it warmed to ambient temperature. The mixture was purified by flash column chromatography (ISCO, 12 g silica, 0-60% ethyl acetate in hexanes) twice to afford 1-3 (602 mg, 1.77 mmol, 88.70% yield).
  • DIAD 647.07 mg, 3.
  • Step 2. 1-3 (300 mg, 884.02 pmol) was dissolved in anhydrous methanol (4.42 mL) and the mixture was cooled to 0 °C in ice bath. NaBPU (334.45 mg, 8.84 mmol) was added slowly over 8 hrs and the mixture was stirred as temperature increases to ambient. The reaction was quenched with cold water (10 mL) and stirred vigorously. The reaction was worked up with DCM (20 mL) and more water (20 mL total) with 5mL of 2N NaOH. Layers were partitioned, and the aqueous layer was extracted 2x with DCM (10 mL). The combined organic layer was washed with brine and dried over sodium sulfate. Llash column chromatography (ISCO, 12 g silica, 0-50% EtOAc in hexanes) provided 1-4 (173.3 mg, 556.61 pmol, 62.96% yield).
  • Step 3 To 1-4 (100 mg, 321.18 pmol) in DCM (1.53 mL) was added Hunig's base (207.55 mg, 1.61 mmol, 279.72 pL). The mixture was cooled to 0 °C and mesyl chloride (73.58 mg, 642.37 pmol, 49.72 pL) was added. The reaction was stirred as temperature increase to ambient over 18 hrs. The reaction was quenched with 2M HC1 (aq) (5mL) at 0 °C. The reaction was diluted with water and DCM (1 OmL each), layers partitioned, and the aqueous layer extracted 2x with DCM (5mL).
  • Step 4 To 1-5 (19.07 mg, 57.81 pmol) in DML (.5 mL), CS2CO3 (56.51 mg, 173.43 pmol) followed by A (20 mg, 69.37 pmol) was added. The mixture was stirred at 23 °C for 4 hrs after which the reaction was diluted with DCM (5 mL) then syringe filtered. The filtrate was concentrated under reduced pressure. Llash column chromatography (ISCO, 12 g silica, 0- 80% ethyl acetate in hexanes) to afford 1-6 (41.8 mg, 71.87 pmol, assumed quantitative with a minor impurity).
  • Step 5 To 1-6 (41.8 mg, 71.87 pmol) in MeOH (0.5 mL) and THE (2 mL), 2M aqueous
  • [0160] 2-2 (5.08 g, 27.58 mmol) was dissolved in methanol (137.92 mL) and cooled to 0 °C in ice bath.
  • NaBH4 (2.09 g, 55.17 mmol) was added slowly under argon and the mixture was stirred as temperature increases over 5 hr. Quenched with water (20mL) and volatiles were removed under reduced pressure to ⁇ 1/3 of its volume. Diluted with water (50mL) and EA (lOOmL) and the layers were partitioned in a separatory funnel. Aqueous layer was extracted twice more with EA (2x50mL). The combined organic layer was washed with brine and dried over sodium sulfate.
  • a (796.97 mg, 2.76 mmol) and CS2CO3 (2.39 g, 7.33 mmol) were combined in DMF (12.22 mL) and 2-4 (0.5 g, 2.44 mmol) was added. Stirred at ambient temperature for 1.5 hr. Diluted with DCM (200mL) and cooled in -20 °C freezer for a half hour, then filtered through a celite pad. Filtrate was transferred to a separatory funnel and 200mL of water added. Layers were partitioned and aqueous layer was extracted twice more with DCM (2xl00mL).
  • Human medulla thyroid carcinoma cell line TT (containing RET C634W mutation) and acute myelogenous cell line KG-1 with FGFR10P2-FGFR1 fusion FGFR 1 gene were purchased from ATCC.
  • Human colon cancer cell line KM12 (containing TPM3-TRKA) was obtained from NCI.
  • the EMF4-AFK gene (variant 1) was synthesized at GenScript and cloned into pCDH- CMV-MCS-EFl-Puro plasmid (System Biosciences, Inc).
  • Ba/F3-EMF4-AFK wild type were generated by transducing Ba/F3 cells with lenti virus containing EMF4-AFK wild type. Stable cell lines were selected by puromycin treatment, followed by IF-3 withdrawal. Briefly, 5 x 10 6 Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8 pg/mF protamine sulfate.
  • the transduced cells were subsequently selected with 1 pg/mF puromycin in the presence of IF3 -containing medium RPMI1640, plus 10% FBS. After 10-12 days of selection, the surviving cells were further selected for IF3 independent growth. [0173]
  • the KIF5B-RET gene was synthesized at GenScript and cloned into pCDH-CMV- MCS-EFl-Puro plasmid (System Biosciences, Inc). KIF5B-RET point mutation V804M and G810R were generated at GenScript by PCR and confirmed by sequencing.
  • Ba/F3 KIF5B-RET wild type and mutants were generated by transducing Ba/F3 cells with lenti virus containing KIF5B-RET wild type or mutants. Stable cell lines were selected by puromycin treatment, followed by IL-3 withdrawal. Briefly, 5 x 10 6 Ba/F3 cells were transduced with lentivirus supernatant in the presence of 8 pg/mL protamine sulfate. The transduced cells were subsequently selected with 1 pg/mL puromycin in the presence of IL3 -containing medium RPMI1640, plus 10% FBS. After 10-12 days of selection, the surviving cells were further selected for IL3 independent growth.

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Abstract

La présente invention concerne certains dérivés macrocycliques, des compositions pharmaceutiques les contenant, et des procédés d'utilisation de ceux-ci pour traiter une maladie, telle que le cancer. L'invention concerne également des procédés d'inhibition de tyrosine kinases réceptrices telles que RET ou SRC à l'aide des dérivés macrocycliques. Les composés macrocycliques ont une fraction noyau hétérocyclique tétracyclique, telle que, cylopenta[5,6][1,4]oxazino[3,4-j]pyrazolo[4,3-g][1,5,9,11]benzoxatriazacyclotétradécin-15-one.
PCT/US2020/037917 2019-06-19 2020-06-16 Macrocycles pour le traitement d'une maladie WO2020257189A1 (fr)

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CN113336774A (zh) * 2021-06-25 2021-09-03 江南大学 作为trk抑制剂的取代的手性二芳基大环化合物
WO2023060022A1 (fr) * 2021-10-05 2023-04-13 Turning Point Therapeutics, Inc. Synthèse de composés macrocycliques

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US20180186813A1 (en) * 2015-07-02 2018-07-05 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
WO2019012093A1 (fr) * 2017-07-14 2019-01-17 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la kinase 2 à répétition riche en leucine
US20190169207A1 (en) * 2014-01-24 2019-06-06 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
WO2019126121A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Composés macrocycliques pour le traitement de maladie

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US20190169207A1 (en) * 2014-01-24 2019-06-06 Tp Therapeutics, Inc. Diaryl macrocycles as modulators of protein kinases
US20180186813A1 (en) * 2015-07-02 2018-07-05 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases
WO2019012093A1 (fr) * 2017-07-14 2019-01-17 Glaxosmithkline Intellectual Property Development Limited Inhibiteurs de la kinase 2 à répétition riche en leucine
WO2019126121A1 (fr) * 2017-12-19 2019-06-27 Tp Therapeutics, Inc. Composés macrocycliques pour le traitement de maladie

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113336774A (zh) * 2021-06-25 2021-09-03 江南大学 作为trk抑制剂的取代的手性二芳基大环化合物
WO2023060022A1 (fr) * 2021-10-05 2023-04-13 Turning Point Therapeutics, Inc. Synthèse de composés macrocycliques

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