WO2021133509A1 - Composés hétérocycliques en tant qu'inhibiteurs de mtor - Google Patents

Composés hétérocycliques en tant qu'inhibiteurs de mtor Download PDF

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Publication number
WO2021133509A1
WO2021133509A1 PCT/US2020/062223 US2020062223W WO2021133509A1 WO 2021133509 A1 WO2021133509 A1 WO 2021133509A1 US 2020062223 W US2020062223 W US 2020062223W WO 2021133509 A1 WO2021133509 A1 WO 2021133509A1
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compound
ring
optionally substituted
substituent
mmol
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PCT/US2020/062223
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English (en)
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Wen-Lian Wu
Zhiqiang Yang
Francis Lee
John Qiang TAN
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Angex Pharmaceutical, Inc.
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Publication of WO2021133509A1 publication Critical patent/WO2021133509A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to heterocyclic compounds, such as 3-(2-((4aS,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl-4((S)-3-methylmorpholino)quinazolin-7-yl)-N- methylbenzamine (1-7), as mTOR inhibitors, and pharmaceutical compositions comprising such compounds.
  • heterocyclic compounds such as 3-(2-(4aS,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl-4((S)-3-methylmorpholino)quinazolin-7-yl)-N- methylbenzamine (1-7), as mTOR inhibitors, and pharmaceutical compositions comprising such compounds.
  • the present disclosure also relates to the use of the compounds and compositions to treat cancer, infectious diseases, and other disorders.
  • mTOR The mammalian target of rapamycin
  • mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORCI) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including cancer, diabetes, and neurodegeneration.
  • mTORCI is a ubiquitously expressed protein complex that controls cell growth by inducing protein and nucleotide synthesis, ribosome biogenesis, and lipogenesis and by blocking autophagy.
  • mTORCI is able to sense environmental signals including growth factors and nutrients and initiates cell growth in favorable environmental conditions. In contrast, unfavorable conditions such as acidity and hypoxia, which are frequently encountered in the tumor microenvironment, inhibit mTORCI activity.
  • unfavorable conditions such as acidity and hypoxia, which are frequently encountered in the tumor microenvironment.
  • PI3K/AKT oncogenic PI3K/AKT
  • RAS/RAF/MEK/MAPK have been well characterized. Activation of these pathways leads to the phosphorylation and inhibition of TSC2 which, in association with TSC1 , forms a protein complex that inhibits mTORCI .
  • TSC tuberous sclerosis complex
  • mTORCI Since mTORCI controls cell growth, it represents a potential target in cancer therapy. mTORCI hyperactivation is furthermore frequently observed in sporadic cancers, either through activating mutations of upstream effectors of mTORCI or through activating mutations of mTOR itself. Additionally, enhanced activation of mTORCI is observed in hamartoma syndromes including Koz-Jeghers syndrome, Cowden disease, and TSC that are characterized by the development of benign tumors and mutations in tumor-suppressor genes that negatively regulate mTORCI activity.
  • AKT a key substrate of mTORC2
  • AKT integrates signals from PI3K/mTORC2 and from PI3K/PDK1 to promote cell growth and survival.
  • PIP3 PTEN null prostate cancer
  • loss of mTORC2 activity inhibits tumorigenesis, illustrating the importance of mTORC2 signaling downstream of PIP3.
  • mTORC2 also regulates cancer cells’ preferential use of glycolysis for energy production through the AKT-independent acetylation of Fox01/3, demonstrating a mTORC2-mediated role in cancer metabolism.
  • AKT activates mTORCI signaling (13,21), adding another layer of complexity to this signaling pathway, genomic alterations, suggesting a distinct role for mTORC2 in cancer as well.
  • heterocyclic compounds comprising pyrido[2,3-d]pyrimidine derivatives, such as a compound of Formula 1, certain optionally substituted 3-(2-((4aS,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted 3-(2-((4aS,7aS)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted N-methyl-3-(4-((S)-3-methylmorpholino)-2- ((4aS,8aR)-octahydro
  • Some embodiments include a compound represented by Formula 1:
  • Ring A is an optionally substituted 4- to 6-membered ring.
  • Ring A is an optionally substituted C 6 aromatic ring, an optionally substituted saturated C 4-6 cyclic hydrocarbon ring, or an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen or ring nitrogen atom.
  • Some embodiments include a method of treating cancer, infectious diseases, and other mTOR-related diseases or disorders comprising administering a subject compound to a patient in need thereof.
  • Some embodiments include use of a subject compound in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other mTOR -related diseases or disorders.
  • kits containing a dosage form that comprises an effective amount of a subject compound for treating cancer, infectious diseases, and other mTOR- related diseases or disorders.
  • the kit may also include written instructions indicating that the dosage form should be used as described herein.
  • Some embodiments include a method of treating a patient in need thereof, having a disease, a disorder, or a condition associated with the inhibition of mTOR kinase, comprising administering a therapeutically effective amount of a subject compound to the patient.
  • the disease is cancer.
  • the disease is an infectious disease.
  • Some embodiments include a pharmaceutical composition comprising a therapeutically effective amount of a subject compound in combination with at least one pharmaceutically acceptable carrier.
  • Some embodiments include a process for synthesizing a subject compound.
  • Some embodiments include a process for making a pharmaceutical composition comprising combining a subject compound and at least one pharmaceutically acceptable carrier.
  • any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts, etc.; or hydrochloride salt, hydrobromide salt, acetic acid salt, and maleic acid salt, etc.; prodrugs, such as ester prodrugs; alternate solid forms, such as polymorphs, solvates, hydrates, etc.; tautomers; or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • pharmaceutically acceptable salts such as sodium, potassium, and ammonium salts, etc.
  • prodrugs such as ester prodrugs
  • alternate solid forms such as polymorphs, solvates, hydrates, etc.
  • tautomers or any other chemical species that may rapidly convert to a compound described herein under conditions in which the compounds are used as described herein.
  • stereochemistry is not indicated, a name or structural depiction includes any stereoisomer or any mixture of stereoisomers.
  • a compound of Formula 1 is a single enantiomer.
  • a compound or chemical structural feature such as aryl when referred to as being “optionally substituted”, it includes a feature that has no substituents (i.e. unsubstituted), or a feature that is “substituted”, meaning that the feature has one or more substituents.
  • substituted is broad; and includes a moiety that occupies a position normally occupied by one or more hydrogen atoms attached to a parent compound or structural feature.
  • a substituent may be an ordinary organic moiety known in the art, which may have a molecular weight (e.g.
  • a substituent comprises, or consists of: 0-30, 0-20, 0-10, or 0-5 carbon atoms; and 0-30, 0-20, 0- 10, or 0-5 heteroatoms, wherein each heteroatom may independently be: N, O, S, P, Si, F, Cl, Br, or I; provided that the substituent includes one C, N, O, S, P, Si, F, Cl, Br, or I atom and N, S and P can be optionally oxidized.
  • substituents include, but are not limited to, deuterium, tritium, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, acyl, acyloxy, alkylcarboxylate, thiol, alkylthio, cyano, halo, thiocarbonyl, O- carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxyl, trihalomethanesulf
  • molecular weight is used with respect to a moiety or part of a molecule to indicate the sum of the atomic masses of the atoms in the moiety or part of a molecule, even though it may not be a complete molecule.
  • the dashed line represents the presence or absence of a double bond
  • any ring carbon is optionally substituted.
  • any or each of the substituents of Ring carbon may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol.
  • Ring carbon may include halo, such as F, Cl, Br, I; hydrocarbyl, such as methyl, C 2 alkyl, C 2 alkenyl, C 2 alkynyl, C 3 alkyl, C 3 cycloalkyl, C 3 alkenyl, C 3 alkynyl, C 4 alkyl, C4 cycloalkyl, C 4 alkenyl, C 4 alkynyl, C 5 alkyl, C 5 cycloalkyl, C 5 alkenyl, C 5 alkynyl, C 6 alkyl, C 6 cycloalkyl, C 6 alkenyl, C 6 alkynyl, phenyl, etc.; CN 0-1 O 0-2 F 0-3 H 0-4 ; C 2 N 0-1 O 0-3 F 0-5 H 0-6 ; C 3 N 0-1 O 0-3 F 0-7 H 0-8 ; C 4 N 0-1 O 0-3 F 0-9
  • R 2a or R 2b is independently H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -NO 2 , -NR A R B , -COR A , -CO 2 R A , -OCOR A , -NR A COR B , or -CONR A R B , etc.
  • R 1a , R 1 b , R 1c , R 1d , R 1e , R 1f , R 19 , R 1 h , R 1 i , R 1j , of R 1 k is independently H or any substituent, such as such as R A , F, Cl, CN, -OR A , CF 3 , -NR A R B , -COR A , -CO 2 R A , -OCOR A , -NR A COR B , or -CONR A R B , etc.
  • R 2a , R 2b , R 1a , R 1 b , R 1c , R 1d , R 1e , R 1f , R 19 , R 1 h , R 1 i , R 1J , or R 1 k may independently be H; F; Cl; CN; CF 3 ; OH; NH 2 ; C 1-6 alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n-propyl, cyclopropyl and isopropyl), cyclopropyl, any one of the butyl isomers, any one of the cyclobutyl isomers (e.g.
  • R 2a , R 2b , R 1a , R 1 b , R 1c , R 1d , R 1e , R 1f , R 19 , R 1 h , R 1 i , R 1j , or R 1 k may independently be H, F, Cl, or CH 3 .
  • R 2a , R 2b , R 1a , R 1 b , R 1c , R 1d , R 1e , R 1f , R 19 , R 1 h , R 1 i , R 1j , or R 1 k may independently be H.
  • R 2a , R 2b , R 1a , R 1 b , R 1c , R 1d , R 1e , R 1f , R 19 , R 1 h , R 1 i , R 1 ’, or R 1 k is F.
  • R 2a , R 2b , R 1a , R 1 b , R 1 c , R 1d , R 1e , R 1f , R 19 , R 1 h , R 1 i , R 1j , or R 1 k may independently be CH 3 .
  • R 2a , R 2b , R 1a , R 1 b , R 1c , R 1d , R 1e , R 1f , R 19 , R 1 h , R 1 i , R 1 ’, and R 1 k may be all H.
  • each R A may independently be H, or C 1 -12 hydrocarbyl, such as C 1 -12 alkyl, C 1 -12 alkenyl, C 1 -12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C a H 2a+1 , or cycloalkyl having a formula C a H 2a-1 , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 11 C, 6 H 13 , C 7 H 15 , C 8 H 17 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl with a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 Hn, C 7 H 13 , C 8 H 15 , C 9 H 17 , C 10 H
  • each R B may independently be H, or C 1 -12 hydrocarbyl, such as C 1 -12 alkyl, C 1 -12 alkenyl, C 1 -12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C a H 2a+1 , or cycloalkyl having a formula C a H 2a-1 , wherein a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, such as linear or branched alkyl with a formula: CH 3 , C 2 H 5 , C 3 H 7 , C 4 H 9 , C 5 H 1 1 , C 6 H 13 , C 7 H 15 , C 8 H 17 , C 9 H 19 , C 10 H 21 , etc., or cycloalkyl with a formula: C 3 H 5 , C 4 H 7 , C 5 H 9 , C 6 H 11 , C 7 H 13 , C 8 H 15 , C 9 H 17 ,
  • Ring A is an optionally substituted 4- to 6-membered ring; and wherein Ring A is an optionally substituted C 6 aromatic ring, an optionally substituted saturated C 4-6 cyclic hydrocarbon ring, or an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen or ring nitrogen atom.
  • any or each of the substituents of Ring A may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol.
  • Ring A may include halo, such as F, Cl, Br, I; hydrocarbyl, such as methyl, C 2 alkyl, C 2 alkenyl, C 2 alkynyl, C 3 alkyl, C 3 cycloalkyl, C 3 alkenyl, C 3 alkynyl, C 4 alkyl, C 4 cycloalkyl, C 4 alkenyl, C 4 alkynyl, C 5 alkyl, C 5 cycloalkyl, C 5 alkenyl, C 5 alkynyl, C 6 alkyl, C 6 cycloalkyl, C 6 alkenyl, C 6 alkynyl, phenyl, etc.; CN 0-1 O 0-2 F 0-3 H0-4; C2N 0-1 O 0-3 F 0-5 H 0-6 ; C 3 N 0-1 O 0-3 F 0-7 H 0-8 ; C 4 N 0-1 O 0-3 F 0-9 H
  • Ring A is an optionally substituted C 6 aromatic ring having 0, 1, 2, 3, or 4 substituents, such as a benzene ring substituted with F, Cl, Br, C 1-6 alkyl, -CO 2 H, , -CN, -CO- C 1-6 alkyl , -C(O)O-C 1-6 alkyl , - C 1-6 alkyl-OH, OH, NH 2 , etc.
  • Ring A is unsubstituted benzene ring.
  • Ring A is an optionally substituted saturated C 4-6 cyclic hydrocarbon ring.
  • Ring A is an optionally substituted saturated C 4 cyclic hydrocarbon ring having 0, 1, 2, 3, 4, 5, or 6 substituents. In some embodiments, Ring A is an optionally substituted saturated C 5 cyclic hydrocarbon ring having 0, 1, 2, 3, 4, 5, 6, 7, or 8 substituents. In some embodiments, Ring A is an optionally substituted saturated C 6 cyclic hydrocarbon ring having 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituents. In some embodiments, Ring A is an optionally substituted cis-cyclopentane-1,2- diyl. In some embodiments, Ring A is an optionally substituted trans-cyclopentane-diyl.
  • Ring A is an optionally substituted cis-cyclohexane-1,2-diyl. In some embodiments, Ring A is an optionally substituted trans-cyclohexane- 1, 2-diyl. In some embodiments, Ring A is an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen or ring nitrogen atom. In some embodiments, Ring A is an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring oxygen atom. In some embodiments, Ring A is an optionally substituted saturated heterocyclic ring containing 4 or 5 ring carbon atoms and 1 ring nitrogen atom.
  • Ring A is an optionally substituted cis-tetrahydrofuran-3,4-diyl. In some embodiments, Ring A is an optionally substituted trans-tetrahydrofuran-3,4-diyl. In some embodiments, Ring A is unsubstituted.
  • the two bonds of Ring A directly attaching to the morpholine ring are in c/s-conformation. In some embodiments, the two bonds of Ring A directly attaching to the morpholine ring are in trans-conformation.
  • Ring A is represented by Formula A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, A11, A12, A13, orA14:
  • R 3 , R 4 , R 5 , or R 6 is independently H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -NO 2 , -NR A R B , -COR A , -CO 2 R a , -OCOR a , -NR A COR b , or -CONR A R B , etc.
  • R 3 , R 4 , R 5 , or R 6 may independently be H, F, Cl, CN, CF 3 , OH, NH 2 , C 1-6 alkyl, or C 1-6 alkoxy.
  • R 3 , R 4 , R 5 , or R 6 may independently be H, F, or Cl. In some embodiments, R 3 , R 4 , R 5 , or R 6 may independently be H. In some embodiments, R 3 , R 4 , R 5 , or R 6 may be F. In some embodiments, R 3 , R 4 , R 5 , and R 6 are all H.
  • R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , or R A1 ° is independently H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -NR A R B , -COR A , -CO 2 R A , -OCOR A , -NR A COR B , or -CONR A R B , etc.
  • R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , or R A10 may independently be H, F, Cl, CN, CF 3 , OH, NH 2 , C1-6 alkyl, or C1-6 alkoxy.
  • R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , or R A1 ° may independently be H.
  • R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , or R A1 ° may independently be F.
  • R A1 , R A2 , R A3 , R A4 , R A5 , R A6 , R A7 , R A8 , R A9 , or R A10 are all H.
  • Ring A may be optionally substituted benzene-1, 2-diyl, optionally substituted cyclopentane-1, 2-diyl, optionally substituted cis-cyclopentane-1, 2-diyl, optionally substituted trans-cyclopentane-diyl, optionally substituted tetrahydrofuran-3,4-diyl, optionally substituted cis-tetrahydrofuran-3,4-diyl, optionally substituted trans-tetrahydrofuran-3,4-diyl, optionally substituted cyclohexane- 1, 2-diyl, optionally substituted cis-cyclohexane-1,2-diyl, optionally substituted trans-cyclohexane-1, 2-diyl, optionally substituted cyclobutane-1, 2-diyl, optionally substituted pyrrolidine-3, 4-di-yl, optionally substituted tetrahydropyr
  • Ring A may be one of the following groups:
  • R 1 is Ci-e alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n-propyl, cyclopropyl and isopropyl), any one of the butyl isomers (e.g. cyclobutyl and methylcyclopropyl), any one of the pentyl isomers, any one of the cyclopentyl isomers, any one of the hexyl isomers, and any one of the cyclohexyl isomers, etc.
  • R 1 is methyl.
  • the ring carbon atom of Formula 1 or 2 directly attaching to R 1 has (S)-configuration.
  • the ring carbon atom directly attaching to R 1 has (R)-configuration.
  • R 2 is an optionally substituted phenyl, or an optionally substituted sulfone methyl group, as represented in Formula 3 and Formula 4 respectfully shown below.
  • R 2 is an optionally substituted phenyl.
  • R 2 is an optionally substituted sulfone methyl group.
  • R 2 is an optionally substituted phenyl having 0, 1, 2, 3, 4, or 5 substituents.
  • R 2 is an optionally substituted sulfone methyl group having 0, 1, 2, 3, or 4 substituents.
  • any or each of the substituents of phenyl or sulfone methyl group as R 2 may have a molecular weight of 15 g/mol to 50 g/mol, 100 g/mol, or 300 g/mol.
  • R 2 may include halo, such as F, Cl, Br, or I; hydrocarbyl, such as methyl, C 2 alkyl, C 2 alkenyl, C 2 alkynyl, C 3 alkyl, C 3 cycloalkyl, C 3 alkenyl, C 3 alkynyl, C 4 alkyl, C 4 cycloalkyl, C 4 alkenyl, C 4 alkynyl, C 5 alkyl, C 5 cycloalkyl, C 5 alkenyl, C 5 alkynyl, C 6 alkyl, C 6 cycloalkyl, Ce alkenyl, Ce alkynyl, or phenyl, etc.; CN 0-1 O 0-2 F 0-3 H 0-4 ; C 2 N 0-1 O 0-3 F 0-5 H 0-6 ; C 3 N 0-1 O 0- 3 F 0-7 H 0-8 ; C 4 N 0-1 O 0-3 F 0-9
  • R 2 is a substituted phenyl and has a -CONHR A substituent, wherein R A is H, C 1-3 alkyl, or cyclopropyl. In some embodiments, R 2 a substituted phenyl which has a -SO 2 R A substituent, wherein R A is H, C 1-3 alkyl, or cyclopropyl. In some embodiments, R 2 is a substituted phenyl which has an optionally substituted 4,5-dihydro-1H-imidazol-2-yl substituent. In some embodiments, R 2 is a substituted phenyl which has a 4,5-dihydro-1H-imidazol-2-yl substituent.
  • R 2 is a substituted phenyl which has a 4, 4-dimethyl-4, 5-dihydro-1H-imidazol- 2-yl substituent. In some embodiments, R 2 is a substituted phenyl which has a F substituent. In some embodiments, R 2 is a substituted phenyl which has a -CONHR A substituent and a F substituent. In some embodiments, R 2 is a sulfone methyl group which has one or two cyclopropyl substituents. In some embodiments, R 2 is methylsulfonylmethyl. In some embodiments, R 2 is (cyclopropylsulfonyl) cyclopropyl.
  • R 2 is represented by Formula 3 or 4:
  • R 3 , R 4 , R 5 , R 6 , or R 7 is independently H or any substituent, such as R A , F, Cl, CN, -OR A , CF3, -NO2, -NR A R B , - COR A , -CO 2 R a , -OCOR a , -NR A COR b , or -CONR A R B , etc.
  • R 3 , R 4 , R 5 , R 6 , or R 7 may be independently H, F -CO(NH)CH 3 , -SO2CH 3 , 4,5-dihydro-1H-imidazol-2-yl, 4- dimethyl-5-dihydro-1H-imidazol-2-yl, or a combination thereof.
  • R 4 may be -CO(NH)CH 3.
  • R 4 may be -SO2CH 3 .
  • R 4 may be 4,5-dihydro-1H-imidazol-2-yl.
  • R 4 may be 4,4-dimethyl-4,5-dihydro-1H- imidazol-2-yl.
  • R 5 is F.
  • R 4 is -CO(NH)CH 3 , and R 5 is F.
  • R 8 , R 9 , R 10 , R 11 , or R 12 may be independently H or any substituent, such as R A , F, Cl, -OH, CF 3 , -NR A R B , etc.
  • R 8 and R 9 together with the carbon atom they attached to form a cyclopropyl ring.
  • R 11 and R 12 together with the carbon atom they attached to form a cyclopropyl ring.
  • R 8 and R 9 together with the carbon atom they attached to form a cyclopropyl ring
  • R 11 and R 12 together with the carbon atom they attached to form a cyclopropyl ring.
  • R 8 and R 9 together with the carbon atom they attached to form a cyclopropyl ring
  • R 11 and R 12 together with the carbon atom they attached to form a cyclopropyl ring
  • R 10 is H.
  • R 8 , R 9 , R 10 , R 11 , or R 12 may be H.
  • R 8 , R 9 , R 10 , R 11 , or R 12 may be CH 3 .
  • R 8 , R 9 , R 10 , R 11 , and R 12 are all H.
  • Some embodiments include optionally substituted 3-(2-((4aS,7aR)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted 3-(2-((4aS,7aS)- hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl)-4-((S)-3-methylmorpholino)pyrido[2,3-d]pyrimidin- 7-yl)-N-methylbenzamide, optionally substituted N-methyl-3-(4-((S)-3-methylmorpholino)-2- ((4aS,8aR)-octahydro-4H-benzo[b][1,4]oxazin-4-yl)pyrido[2,3-d]pyr
  • Some embodiments include one of the compounds listed in Table 1 below, wherein each structure can be optionally substituted:
  • a pharmaceutical composition comprising a subject compound may be adapted for oral, or parental, such as intravenous, intramuscular, topical, intraperitoneal, nasal, buccal, sublingual, or subcutaneous administration, or for administration via respiratory tract in the form of, for example, an aerosol or an air-suspended fine powder.
  • the dosage of a subject compound may vary depending on the route of administration, body weight, age, the type and condition of the disease being treated.
  • a pharmaceutical composition provided herein may optionally comprise two or more subject compounds without an additional therapeutic agent, or may comprise an additional therapeutic agent (i.e. , a therapeutic agent other than a compound provided herein).
  • the compounds of the disclosure can be used in combination with at least one other therapeutic agent.
  • Therapeutic agents include, but are not limited to antibiotics, antiemetic agents, antidepressants, and antifungal agents, anti-inflammatory agents, antiviral agents, and anticancer agents that are known in the art.
  • the pharmaceutical composition may be used for the treatment of cancer, and other mTOR-related diseases or disorders in patients.
  • patient herein means a mammal (e.g., a human or an animal). In some embodiments, the patient has cancer.
  • the pharmaceutical composition described herein can be prepared by combining a compound of Formula 1 with at least one pharmaceutical acceptable inert ingredient, such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc., selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • a pharmaceutical acceptable inert ingredient such as a carrier, excipient, filler, lubricant, flavoring agent, buffer, etc.
  • the relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.
  • Some embodiments include a method of treating a disease or disorder associated with mTOR comprising administering a therapeutically effective amount of a compound of Formula 1 or a pharmaceutical composition comprising a compound of Formula 1 to a patient in need thereof.
  • a therapeutically effective amount herein refers to an amount of a compound or a pharmaceutical composition of the present disclosure provided herein sufficient to be effective in inhibiting mTOR enzyme and thus providing a benefit in the treatment of cancer, infectious diseases and other mTOR associated disorders, to delay or minimize symptoms associated with cancer, infectious diseases and other mTOR associated disorders, or to ameliorate a disease or infection or cause thereof.
  • about 0.01-1000 mg of a subject compound may be a therapeutically effective amount.
  • treatment refers to causing a therapeutically beneficial effect, such as ameliorating existing symptoms, ameliorating the underlying causes of symptoms, postponing, preventing the further development of a disorder, or reducing the severity of symptoms that are otherwise expected to develop without treatment.
  • kits containing an effective therapeutic amount of a subject compound and a label with instructions to use the subject compound, or a composition or dosage form containing an effective therapeutic amount of the subject compound, for the treatment of cancer, infectious diseases, and/or other mTOR related disorders.
  • the compounds of the disclosure can be made using procedures known in the art.
  • the following reaction schemes show typical procedures, but those skilled in the art will recognize that other procedures can also be suitable for using to prepare these compounds.
  • R 1 or R 2 is not hydrogen
  • changes to the requisite reagents can be made at the appropriate steps in the synthetic methods outlined below.
  • Reactions may involve monitoring for consumption of starting materials, and there are many methods for the monitoring, including but not limited to thin layer chromatography (TLC) and liquid chromatography mass spectrometry (LCMS).
  • TLC thin layer chromatography
  • LCMS liquid chromatography mass spectrometry
  • Microliter ⁇ L
  • Micrometer ⁇ m Milligram: mg Milliliter: mL
  • Tetrahydrofuran THF Thin layer chromatography: TLC p-Toluenesulfonic acid: TsOH Triethylamine: Et 3 N or TEA Trifluoroacetic acid: TFA
  • Analytical thin layer chromatography was performed on glass plates pre-coated with silica gel 60 F254 0.25 mm plates (EM Science), and visualized with UV light (254 nm) and/ or heating with commercial ethanolic phosphomolybdic acid, preparative thin layer chromatography (TLC) was performed on glass-plates pre-coated with silica gel 60 F254 0.5 mm plates (20 x 20 cm, from commercial sources) and visualized with UV light (254 nm).
  • NMR spectra and 13 C-NMR were recorded on a Varian Mercury-VX400 instrument operating at 400 MHZ.
  • NMR spectra were obtained as CDCI 3 solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm for the proton and 77.00 ppm for carbon), CD 3 OD (3.4 and 4.8 ppm for the protons and 49.3 ppm for carbon), DMSO-d 6 (2.49 ppm for proton), or internally tetramethylsilane (0.00 ppm) when appropriate.
  • Other NMR solvents were used as needed.
  • Step 2 To a stirred solution of 73.0 g (412 mmol) of compound 1-1 in 400 mL of THF was added 155 g (1240 mmol) of SOCI 2 dropwise at 0 °C. The mixture was stirred at 60 °C for 2 h and concentrated under vacuum to give a residue. It was dissolved with 400 mL of THF and added dropwise into a 3 L 3-necked round-bottom flask containing 650 mL of NH 3 (7M in MeOH). The solution was stirred at RT for additional 2 h, the solids were filtered out and the filtrate was concentrated. The residue was diluted with water and extracted with two 300 mL portions of ethyl acetate.
  • Step 6 To a stirred solution of 7.00 g (23.4 mmol) of compound 1-5 in 100 mL of dioxane and 10 mL of H 2 O were added 6.72 g (25.7 mmol) of intermediate 14, 4.96 g (46.8 mmol) of Na 2 CO 3 and 1.71 g (2.3 mmol) of Pd(dppf)Cl 2 in portions at RT under nitrogen atmosphere. The mixture was stirred at 90 °C for 3 h and cooled to RT. The reaction was quenched with water and extracted with two 50 mL portions of EA. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4 .
  • step 7 the following analogs in Table 2 were prepared from compound 1-6 by employing the requisite bicyclic amines.
  • Other compounds of Formula 1 may be prepared in a similar way.
  • Step 1-3 Compound 14 was prepared from 3-bromobenzoic acid following the 3-step reaction sequences described in Scheme 7.
  • LC-MS: m/e 262 [M+H] + .
  • MSP Meso Scale Discovery
  • the cells in the wells were lysed with the MSD lysis buffer on a 4 °C shaker for 30 min.
  • 150 pL of Blocking Buffer was added to each well of MSD plate.
  • the plate was sealed with an adhesive plate seal and incubated for 1 hour with vigorous shaking (300-1000 rpm) at room temperature.
  • MSD plate was washed 3 time with 150 ⁇ L/well 1X Tris wash buffer.
  • 25 ⁇ L/well of cell lysate was transferred from cell culture plate to the MSD plate.
  • the plate was sealed with an adhesive plate seal and incubated for 1 hour with vigorous shaking (300-1000 rpm) at room temperature.
  • MSD plate was washed 3 time with 150 ⁇ L/well 1X Tris wash buffer.
  • MSD plate 25 ⁇ l/well Detection Antibody Solution was added to the wells of MSD plate. The plate was sealed with an adhesive plate seal and incubated for 1 hour with vigorous shaking (300-1000 rpm) at room temperature. MSD plate was washed 3 time with 150 ⁇ L/well 1X Tris wash buffer. 150 ⁇ L/well of 1X Read Buffer T was added to each well of the MSD plate. Electrochemiluminescence was recorded by MSD QuickPlex SQ 120. Phospho-Akt(Ser473), phospho-p70S6K (Thr389), and Phospho-4E-BP1 (Thr37/46) expression graphs were plotted with GraphPad Prism 4 program . The testing results for selected compounds are summarized in Table 4.
  • *AZD2014 is a reference compound, which has CAS# [1009298-59-2]
  • **NA means that the data is not yet available.

Abstract

La présente invention concerne de nouveaux inhibiteurs hétérocycliques de mTOR et leurs procédés de préparation. L'invention concerne également les compositions pharmaceutiques comprenant de tels inhibiteurs de mTOR et des procédés d'utilisation de celles-ci pour le traitement du cancer, de maladies infectieuses et d'autres troubles associés à mTOR.
PCT/US2020/062223 2019-12-27 2020-11-25 Composés hétérocycliques en tant qu'inhibiteurs de mtor WO2021133509A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008023161A1 (fr) * 2006-08-23 2008-02-28 Kudos Pharmaceuticals Limited Dérivés de la 2-méthylmorpholine pyrido-, pyrazo- et pyrimido-pyrimidine en tant qu'inhibiteurs de mtor
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
WO2019180141A1 (fr) * 2018-03-23 2019-09-26 Bayer Aktiengesellschaft Combinaisons de rogaratinib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080194546A1 (en) * 2005-11-22 2008-08-14 Kudos Pharmaceuticals Limited Pyrido-, Pyrazo- and Pyrimido-Pyrimidine Derivatives as mTOR Inhibitors
WO2008023161A1 (fr) * 2006-08-23 2008-02-28 Kudos Pharmaceuticals Limited Dérivés de la 2-méthylmorpholine pyrido-, pyrazo- et pyrimido-pyrimidine en tant qu'inhibiteurs de mtor
WO2019180141A1 (fr) * 2018-03-23 2019-09-26 Bayer Aktiengesellschaft Combinaisons de rogaratinib

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Pubmed U.S. National Library of Medicine; 27 October 2008 (2008-10-27), "5-{2-(2.3-Dihydro-1 3-methylmorpholin-4-yl]pyrido[2,3-dlpyrimidin-7-yll-2-methoxyphenyl]methanol", Database accession no. 24998807 *

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