WO2020243178A1 - Composés hétérocycliques en tant qu'inhibiteurs de prmt5 - Google Patents

Composés hétérocycliques en tant qu'inhibiteurs de prmt5 Download PDF

Info

Publication number
WO2020243178A1
WO2020243178A1 PCT/US2020/034711 US2020034711W WO2020243178A1 WO 2020243178 A1 WO2020243178 A1 WO 2020243178A1 US 2020034711 W US2020034711 W US 2020034711W WO 2020243178 A1 WO2020243178 A1 WO 2020243178A1
Authority
WO
WIPO (PCT)
Prior art keywords
optionally substituted
compound
pyrrolo
quinolin
ethyl
Prior art date
Application number
PCT/US2020/034711
Other languages
English (en)
Inventor
Wen-Lian Wu
Zhiqiang Yang
Francis Lee
John Qiang TAN
Original Assignee
Angex Pharmaceutical, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Angex Pharmaceutical, Inc. filed Critical Angex Pharmaceutical, Inc.
Priority to AU2020283505A priority Critical patent/AU2020283505A1/en
Priority to JP2021570954A priority patent/JP2022534998A/ja
Priority to CA3141855A priority patent/CA3141855A1/fr
Priority to KR1020217043087A priority patent/KR20220016194A/ko
Priority to EP20814821.3A priority patent/EP3976038A4/fr
Priority to CN202080052198.1A priority patent/CN114126614A/zh
Publication of WO2020243178A1 publication Critical patent/WO2020243178A1/fr
Priority to US17/532,964 priority patent/US20220089612A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/14—Pyrrolo-pyrimidine radicals

Definitions

  • the present disclosure relates to heterocyclic compounds, such as (1 R,2S,3R,5S)-3-(4- amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(2-(2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)- cyclopentane-1 ,2-diol (1-7), as PRMT5 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.
  • PRMT5 Protein arginine N-methyltransferase 5
  • Skb1 Schizosaccharomyces pombe
  • Hsl7 Sacharomyces cerevisiae
  • PRMT5 catalyzes the transfer of methyl group from the essential co-factor S-adenosylmethionine to methylate the arginine N-guanidine group of various proteins.
  • Substrate proteins for PRMT5 include histones, transcriptional elongation factors, kinases, and tumor suppressors, for example, histone H4, histone H3, and non-histone proteins such as FGF-216, NF-kB17, HOXA918, and p53.
  • PRMT5 is involved in the transcriptional repression of a number of tumor suppressor genes including suppressor of tumorigenicity 7 (ST7), nonmetastatic 23 (NM23), retinoblastoma (Rb) family, and programmed cell death 4 (PDCD4).
  • ST7 suppressor of tumorigenicity 7
  • NM23 nonmetastatic 23
  • Rb retinoblastoma
  • PDCD4 programmed cell death 4
  • PRMT5 has recently emerged as a promising drug target due to its frequent overexpression in a variety of malignancies including glioma, lung cancer, melanoma, mantle cell lymphoma, multiple endocrine neoplasia, prostate and gastric cancer, as well as its synthetic lethal relationship with methylthioadenosine phosphorylase (MTAP).
  • MTAP methylthioadenosine phosphorylase
  • PRMT5 localization differs between normal and tumor tissues and l between tumor subtypes. This is indicative that its compartment-specific functions likely regulate distinct molecular programs and are therefore associated with diverse phenotypic outcomes.
  • the identification and development of small-molecules that inhibit PRMT5 activity will serve as therapeutic approach for the treatment of a variety of PRMT5-related diseases or disorders, such as cancer.
  • This disclosure relates to heterocyclic compounds comprising at least three ring systems, such as a compound of Formula 1 , certain optionally substituted (1 S,2R,3S,5R)-3-(2- (2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7- yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(2,3-dihydroimidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(imidazo[1 ,2-c]quinazolin-8-yl)eth
  • Some embodiments include a compound represented by Formula 1 :
  • (Rinqg A)) is an optionally substituted 4-amino-7F/-pyrrolo[2,3-d]pyrimidin-7-yl ;
  • (Ring B) is an optionally substituted fused tricyclic heterocyclic ring system containing 1 , 2, 3, 4, or 5 ring N atoms, 0 or 1 ring 0 atom, and a fused benzene ring, wherein the fused benzene ring is directly attached to L;
  • X is - 0-, -CH2-, or -CF2-;
  • L is optionally substituted Ci-3 hydrocarbylene, optionally substituted -O-C1-2 hydrocarbylene-, optionally substituted -S-C1-2 hydrocarbylene-, or optionally substituted -NR A - C1-2 hydrocarbylene; and
  • R A is H, Ci- 6 hydrocarbyl, C1-6 heteroaryl, C1-6 heterocycloalkyl, -C(O)- C1-6 alkyl,
  • Some embodiments include use of a compound described herein, such as a subject compound in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other PRMT5 related disorders.
  • 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 making a pharmaceutical composition comprising combining a subject compound and at least one pharmaceutically acceptable carrier.
  • Some embodiments include a method of treating cancer, infectious diseases, and other PRMT5 related 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 PRMT5 related disorders.
  • kits containing a subject compound and a label with instructions to use the subject compound, or a composition or dosage form containing the subject compound, for the treatment of cancer, infectious diseases, and other PRMT5 related disorders.
  • any reference to a compound herein by structure, name, or any other means includes pharmaceutically acceptable salts, such as sodium, potassium, and ammonium salts; 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
  • prodrugs such as ester prodrugs
  • 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.
  • a compound of Formula 1 is a single enantiomer.
  • a subject compound described herein contains one or more deuterium.
  • 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.
  • the term“substituent” 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, trihalomethanes
  • moiety or part of a molecule indicates 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.
  • Ring A and Ring B The structures associated with some of the chemical names referred to herein, such as Ring A and Ring B, are depicted below. These structures may be unsubstituted, as shown below, or substituted with a substituent that may independently be in any position normally occupied by a hydrogen atom when the structure is unsubstituted. Unless a point of attachment is indicated by i , attachment may occur at any position normally occupied by a hydrogen atom.
  • Ring A of Formula 1 comprises:
  • each R is independently H, F, Cl, Br, I, -NR A R B , Ci-e hydrocarbyl, -OH, -CN, or -O-Ci-e alkyl; and wherein each R A and each R B are independently H, Ci-e hydrocarbyl, Ci -e heteroaryl, Ci - 6 heterocycloalkyl, -C(0)-Ci-e alkyl, -C(0)NH-CI- 6 alkyl, or -C(0)0Ci-e alkyl.
  • Ring A is an optionally substituted 4-amino-7F/-pyrrolo[2,3-d]pyrimidin-7-yl.
  • any or each of the substituents of Ring A may have a molecular weight of at least 15 g/mol, and up to: 50 g/mol, 60 g/mol, 70 g/mol, 80 g/mol, 90 g/mol, 100 g/mol, or 300 g/mol.
  • Ring A may include -OH; -CN; 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, Ce alkenyl, Ce alkynyl, phenyl, etc.; CN0-1O0-2F0-3H0-4; C2N0-1O0-3F0-5H0-6; C3N0-1O0-3F0- 7 HO- 8 ; C4N0-1O0-3F0-9H0-10; C5N0-1O
  • Ring A is optionally substituted 4-amino-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl having 1 , 2, or 3 substituents, such as 4-amino-7/-/-pyrrolo[2,3-d]pyrimidin-7-yl substituted with F, Cl, Br, Ci-e alkyl, -CO 2 H, , -CN, -CO-Ci-e-alkyl, -C(0)0-Ci- 6 -alkyl, C 1-6 alkyl-OH, OH, NH 2 , etc..
  • Ring A is unsubstituted 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl.
  • Ring A1 is represented by Formula A1 :
  • R 1 is H or any substituent, such as R A , F, Cl, -CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc., wherein R A and R B are each H, Ci- 6 hydrocarbyl, Ci - 6 heteroaryl, Ci - 6 heterocycloalkyl, -C(0)-Ci- 6 alkyl, -C(0)NH-CI-6 alkyl, or -C(0)0Ci-s alkyl.
  • R 1 may be H; F; Cl; -CN; CF 3 ; OH; NH 2 ; Ci-s alkyl, such as methyl, ethyl, any one of the propyl isomers (e.g. n- propyl and isopropyl), cyclopropyl, any one of the butyl isomers, any one of the cyclobutyl isomers (e.g.
  • R 1 may be H, F, Cl, or NH 2 .
  • R 1 may be H, F, Cl, or NH 2 .
  • each R A1 may independently be H, or C1-12 hydrocarbyl, such as C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C a H2 a+i , or cycloalkyl having a formula C a H2 a -i , 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 , C2H5, C3H7, C4H9, C5H11 , OdH , C7H15, CSH I , C9H 19, C10H21 , etc., or cycloalkyl with a formula: C 3 H 5 , C4H7, C5H9, CeHn , C7HI 3 , C 3 Hi5, C9H 17, C10H 19, etc.
  • R A1 may be H or C1-6 alkyl. In some embodiments, R A1 may be H or Ci- 3 alkyl. In some embodiments, R A1 may be H or CH 3 . In some embodiments, R A1 may be H.
  • each R B1 may independently be H, or C1-12 hydrocarbyl, such as C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, phenyl, etc., including: linear or branched alkyl having a formula C a H2 a+i , or cycloalkyl having a formula C a H2 a -i , 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 , C2H5, C 3 H 7 , C4H9, C5H11 , OdHi 3 , C7H15, CeH ⁇ , C9H 19, C10H21 , etc., or cycloalkyl with a formula: C 3 H 5 , C4H7, C5H9, CeHn , C7HI 3 , CsHis, C9H 17, C10H 19, etc.
  • R 2 is H or any substituent, such as R A , F, Cl, -CN, -OR A , CF 3 , -NO2, -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
  • R 2 may be H, F, Cl, CN, CF 3 , OH, NH2, C1-6 alkyl, or Ci-e alkoxy.
  • R 2 may be H, F, Cl, or NH2.
  • R 2 may be H.
  • R 3 is H or any substituent, such as R A , F, Cl, -CN, -OR A , CF 3 , -NO2, -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
  • R 3 may be H, F, Cl, -CN, CF 3 , OH, NH 2 ,
  • R 3 may be H, F, Cl, or NH . In some embodiments, R 3 may be H. [028] With respect to any relevant structural representation, such as Formula A1 , in some embodiments, both R A and R B are H. In some embodiments, R 1 , R 2 , and R 3 are all H. In some embodiments, R A , R B , R 1 , R 2 , and R 3 are all H.
  • Ring B is an optionally substituted fused tricyclic heterocyclic ring system containing 1 , 2, 3, 4, or 5 ring N atoms, 0 or 1 ring 0 atom, and a fused benzene ring, wherein the fused benzene ring is directly attached to L.
  • any or each of the substituents of Ring B may have a molecular weight of 15 g/mol to 50 g/mol, 50 g/mol to 100 g/mol, 50 g/mol to 75 g/mol, 75 g/mol to 100 g/mol, or 100 g/mol to 300 g/mol.
  • Ring B may include halo, such as F, Cl, Br, or I; hydrocarbyl, such as methyl, C2 alkyl, C2 alkenyl, C2 alkynyl, C3 alkyl, C3 cycloalkyl, C3 alkenyl, C3 alkynyl, C4 alkyl, C4 cycloalkyl, C4 alkenyl, C4 alkynyl, C5 alkyl, C5 cycloalkyl, C5 alkenyl, C5 alkynyl, Ce alkyl, Ce cycloalkyl, Ce alkenyl, Ce alkynyl, or phenyl, etc.; CN0-1O0-2F0-3H0-4; C2 N 0- 10o-3 FO-5 H 0-6 i C3N0-1O0-3F0-7H0-8; C4N0-1O0-3F0-9H0-I0; C5N0-1O0-3F0-H Ho-12;
  • Ring B is optionally substituted 2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8- yl, optionally substituted 1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 H-pyrazolo[3,4- b]quinolin-7-yl, optionally substituted 3H-imidazo[4,5-b]quinolin-6-yl, optionally substituted 3H- [1 ,2,3]triazolo[4,5-b]quinolin-6-yl, optionally substituted 2,3-dihydroimidazo[1 ,2-c]quinazolin-8- yl, optionally substituted imidazo[1 ,2-c]quinazolin-8-yl, optionally substituted (1aS,7bR)-1a
  • Ring B is optionally substituted 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl having 0, 1 , 2, or 3, 4, 5, 6, 7, 8, or 9 substituents, such as 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl substituted with F, Cl, Br, C1-6 alkyl, -CO2H, -CN, -CO-Ci- 6 -alkyl, -C(0)0-Ci- 6 -alkyl, -C1-6 alkyl- OH, OH, NH2, etc.
  • Ring B is 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl having 2 substituents. In some embodiments, Ring B is 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7- yl having 1 substituent. In some embodiments, Ring B is unsubstituted 2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl. In some embodiments, Ring B is 2,3-dihydro-1 H-pyrrolo[2,3- b]quinolin-7-yl having 2 substituents that are both methyl groups.
  • Ring B is 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl having 2 substituents at a same ring carbon atom that are two methylene groups linked together and together with the ring carbon atom to which they are attached to form a spiro cyclopropyl.
  • Ring B is 2,3-dihydro-1 H-pyrrolo[2,3- b]quinolin-7-yl having 1 substituent that is methyl.
  • Ring B is optionally substituted 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 0, 1 , 2, or 3, 4, 5, 6, 7, 8, 9, 10, or 1 1 substituents, such as 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl substituted with F, Cl, Br, Ci- 6 alkyl, -C0 2 H, -CN, -CO-Ci- 6 -alkyl, -C(0)0-Ci- 6 -alkyl, -Ci- 6 alkyl-OH, OH, NH 2 , etc.
  • Ring B is 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 2 substituents. In some embodiments, Ring B is 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent. In some embodiments, Ring B is unsubstituted 1 , 2,3,4- tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
  • Ring B is 1 , 2,3,4- tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent that is methyl or cyclopropyl. In some embodiments, Ring B is 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent that is methyl. In some embodiments, Ring B is 1 ,2,3,4- tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl having 1 substituent that is cyclopropyl.
  • Ring B is 3,4-dihydro-1 H-[1 ,2]oxazino[3,4-b]quinolin-8-yl. In some embodiments, Ring B is 1 ,3-dihydroisoxazolo[3,4-b]quinolin-7-yl. In some embodiments, Ring B is 3H- imidazo[4,5-b]quinolin-6-yl. In some embodiments, Ring B is 2,3,4,5-tetrahydro-1 H-azepino[2,3- b]quinolin-9-yl.
  • Ring B is:
  • each structure is optionally substituted;
  • G is N or CR; the dashed line represents optionally with or without a bond;
  • Y is -N(R A )-, N, C(R C ), -C(R C R D )-, or -C(R c R D )-C(R c R D )-;
  • Z is a bond, -N(R A )-, N, C(R C ), or -C(R c R D )-;
  • Ring B is represented by Formula 2 or 3:
  • W and Z are linked by a single bond.
  • Y and Z are linked by a double bond.
  • WZ is -CH2-CH2-.
  • WZ is - OCH2-,
  • R 4 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
  • R 4 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci- 6 alkyl, or Ci-e alkoxy.
  • R 4 may be H, F, or Cl.
  • R 4 may be H.
  • R 5 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
  • R 5 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci-e alkyl, or Ci-e alkoxy.
  • R 5 may be H, F, or Cl.
  • R 5 may be H.
  • R 6 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
  • R 6 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci-e alkyl, or Ci-e alkoxy.
  • R 6 may be H, F, or Cl.
  • R 6 may be H.
  • R 7 is H or any substituent, such as R A , F, Cl, CN, -OR A , CF 3 , -N0 2 , -NR A R B , -COR A , -C0 2 R A , -OCOR A , - NR A COR B , or -CONR A R B , etc.
  • R 7 may be H, F, Cl, CN, CF 3 , OH, NH 2 , Ci-e alkyl, or Ci-e alkoxy.
  • R 7 may be H, F, or Cl.
  • R 7 may be H.
  • R A1 is H or Ci-i 2 hydrocarbyl.
  • R A1 may be H or Ci-e alkyl.
  • R A1 may be H or Ci- 3 alkyl.
  • R A1 may be H or CH 3 .
  • R A1 may be H.
  • Z is a bond, -N(R A )-, or -C(R c R D )-. In some embodiments, Z is -C(R c R D )-. In some embodiments, Z is -N(R A )-. In some embodiments, Z is -N-. In some embodiments, Z is -CH 2 -. In some embodiments, Z is CH. In some embodiments, Z is a bond.
  • W is a bond, -N(R A )-, N, -0-, C(R C ), or -C(R C R D )-.
  • W is -C(R C R D )-.
  • W is -N(R A )-.
  • W is N.
  • W is C(R C ).
  • W is -CH-.
  • W is CH 2 .
  • W is a bond.
  • W is -0-.
  • G is N or CR. In some embodiments, G is N. In some embodiments, G is CR. In some embodiments, G is CH.
  • both W and Z are a bond, and G is CH.
  • X is -0-, -CH 2 - , or -CF 2 -. In some embodiments, X is -CF 2 -. In some embodiments, X is -0-. In some embodiments, X is -CH 2 -.
  • L is C 1-3 hydrocarbylene.
  • L is -0-Ci- 2 hydrocarbylene-.
  • L is -S-Ci- 2 hydrocarbylene-. In some embodiments, L is -NR A -CI- 2 hydrocarbylene-. In some embodiments, L is -CH 2 -CH 2 -CH 2 -. In some embodiments, L is -CH 2 - CH 2 -.
  • Some embodiments include a compound represented by Formula 4 or 5 below:
  • Formula 4 and 5 may be unsubstituted as shown, or the 4-amino-7H-pyrrolo[2,3- d]pyrimidin-7-yl may have 1 , 2, or 3 substituents, such as those described elsewhere herein, or may be substituted at any position, such as those described elsewhere herein.
  • Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(2,3- dihydroimidazo[1 ,2-c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2- diol.
  • Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(imidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-((1aS,7bR)-1a,7b- dihydro-1 H-cyclopropa[c]quinolin-5-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane- 1 ,2-diol.
  • Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-((1aR,7bS)-1a,7b- dihydro-1 H-cyclopropa[c]quinolin-5-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane- 1 ,2-diol.
  • Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(1 H-pyrazolo[3,4- b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(2,3-dihydro-1 H- pyrrolo[2,3-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.
  • Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(2,3- dihydroimidazo[1 ,2-c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-
  • Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(imidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.
  • Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(1 H-pyrrolo[2,3- b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(3,4-dihydro-1 H- [1 ,2]oxazino[3,4-b]quinolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(1 ,3- dihydroisoxazolo[3,4-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2- diol.
  • Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,3,4,5-tetrahydro-[1 ,2]oxazepino[3,4-b]quinolin-9-yl)ethyl)cyclopentane- 1 ,2-diol.
  • Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(3H-imidazo[4,5- b]quinolin-6-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (1S,2R,3S,5R)-3-(2-(3H- [1 ,2,3]triazolo[4,5-b]quinolin-6-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (1 S,2R,3S,5R)-3-(2-(2,3-dihydro-1 H- pyrazolo[3,4-b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol.
  • Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl)ethyl)cyclopentane-1 ,2- diol.
  • Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(2,3,4,5-tetrahydro-1 H-azepino[2,3-b]quinolin-9-yl)ethyl)cyclopentane-1 ,2- diol.
  • Some embodiments include optionally substituted (2R,3S,4R,5R)-2-(2-(1 H-pyrazolo[3,4- b]quinolin-7-yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)tetrahydrofuran-3,4-diol.
  • Some embodiments include optionally substituted (2R,3R,4S,5R)-2-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl)ethyl)tetrahydrofuran-
  • Some embodiments include optionally substituted (1 R,2S,3R,5S)-3-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)-5-(2-(1 ,2,3,4-tetrahydropyridazino[3,4-b]quinolin-8-yl)ethyl)cyclopentane-1 ,2- diol.
  • Some embodiments include one of the compounds listed in Table 1 below, wherein each structure can be optionally substituted.
  • Some embodiments include one of the compounds listed in Table 1a below, wherein each structure can be optionally substituted.
  • Some embodiments include use of a subject compound in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other PRMT5 related disorders.
  • 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 PRMT5-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 PRMT5 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 PRMT5 enzyme and thus providing a benefit in the treatment of cancer, infectious diseases and other PRMT5 associated disorders, to delay or minimize symptoms associated with cancer, infectious diseases and other PRMT5 associated disorders, or to ameliorate a disease or infection or cause thereof (e.g. 0.1-1000 mg).
  • 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.
  • Embodiment 1 A compound represented by a formula:
  • (Ring A) is an optionally substituted 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl
  • (Ring B) is an optionally substituted fused tricyclic heterocyclic ring system containing 1 , 2, 3, 4, or 5 ring N atoms, 0 or 1 ring 0 atom, and a fused benzene ring, wherein the fused benzene ring is directly attached to L;
  • X is -0-, -CH 2 -, or -CF 2 -;
  • L is optionally substituted C 1.3 hydrocarbylene, optionally substituted -0-Ci- 2 hydrocarbylene-, optionally substituted -S-Ci- 2 hydrocarbylene-, or optionally substituted -NR A -C I-2 hydrocarbylene-;
  • R A is H, C hydrocarbyl, Ci-e heteroaryl, Ci-e heterocycloalkyl, -C(0)-Ci- 6 alkyl, -C(0)NH-CI- 6 alkyl, or -C(0)0Ci- 6 alkyl.
  • Embodiment 2 The compound of embodiment 1 , wherein Ring A comprises:
  • Ring B comprises: wherein each structure is optionally substituted
  • G is N or CR
  • Y is -N(R A )-, N, C(R c ), or -C(R c R D )-, or -C(R c R D )-C(R c R D )-;
  • Z is a bond, -N(R A )-, N, C(R C ), or -C(R c R D )-;
  • W is a bond, -N(R A )-, N, -0-, C(R C ), or -C(R C R D )-;
  • dashed line represents optionally with or without a bond
  • each R A and each R B are independently H, C1-6 hydrocarbyl, C1-6 heteroaryl, C1-6 heterocycloalkyl, -C(0)-Ci- 6 alkyl, -C(0)NH-Ci-e alkyl, or -C(0)0Ci-e alkyl; and wherein each R, each R A , each R B , each R c , and each R D are independently optionally halogenated.
  • Embodiment 3 The compound of embodiment 1 or 2, wherein Ring A comprises unsubstituted 4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl.
  • Embodiment 4 The compound of embodiment 1 , 2, or 3, wherein the optionally substituted fused tricyclic heterocyclic ring system of Ring B is an optionally substituted fused tricyclic heteroaromatic ring system.
  • Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains one ring N atom.
  • Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains two ring N atoms.
  • Embodiment 7. The compound of embodiment 1 , 2, or 3, wherein Ring B contains three ring N atoms.
  • Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains four ring N atoms.
  • Embodiment s The compound of embodiment 1 , 2, or 3, wherein Ring B contains one ring 0 atom.
  • Embodiment 10 The compound of embodiment 1 , 2, or 3, wherein Ring B is optionally substituted 2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 3,3-dimethyl-2,3- dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 H-pyrrolo[2,3-b]quinolin-7-yl, optionally substituted 1 H-pyrazolo[3,4-b]quinolin-7-yl, optionally substituted 5-amino-2,3- dihydroimidazo[1 ,2-c]quinazolin-8-yl, optionally substituted 5-aminoimidazo[1 ,2-c]quinazolin-8-yl, optionally substituted (1aS,7bR)-2-amino-1 a,7b-dihydro-1 H-cyclopropa[c]quinolin-5-yl, optionally substituted (1aR,7b
  • Embodiment 12 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 3,3-dimethyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 13 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 14 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 1 H-pyrazolo[3,4-b]quinolin-7-yl.
  • Embodiment 15 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 5-amino-2,3-dihydroimidazo[1 ,2-c]quinazolin-8-yl.
  • Embodiment 16 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 5-aminoimidazo[1 ,2-c]quinazolin-8-yl.
  • Embodiment 17 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (1 aS,7bR)-2-amino-1a,7b-dihydro-1 H-cyclopropa[c]quinolin-5-yl.
  • Embodiment 18 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (1 aR,7bS)-2-amino-1a,7b-dihydro-1 H-cyclopropa[c]quinolin-5-yl.
  • Embodiment 19 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 3,4-dihydro-1 H-[1 ,2]oxazino[3,4-b]quinolin-8-yl.
  • Embodiment 20 The compound of embodiment 1 , 2, or 3, wherein Ring comprises optionally substituted 1 ,3-dihydroisoxazolo[3,4-b]quinolin-7-yl.
  • Embodiment 21 The compound of embodiment 1 , 2, or 3, wherein Ring comprises optionally substituted (R)-3-methyl-3,4-dihydro-1 H-[1 ,2]oxazino[3,4-b]quinolin-8-yl
  • Embodiment 22 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 3H-imidazo[4,5-b]quinolin-6-yl.
  • Embodiment 23 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 24 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-methyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 25 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-cyclopropyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 26 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-cyclopropyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 27 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-ethyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 28 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-isopropyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 29 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-(tert-butyl)-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 30 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-allyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 31 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 2,2-dimethyl-2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7-yl.
  • Embodiment 32 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted T,3'-dihydrospiro[cyclopropane-1 ,2'-pyrrolo[2,3-b]quinolin]-7'-yl.
  • Embodiment 33 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
  • Embodiment 34 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-methyl-1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
  • Embodiment 35 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (R)-2-methyl-1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
  • Embodiment 36 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted (S)-2-cyclopropyl-1 ,2,3,4-tetrahydrobenzo[b][1 ,8]naphthyridin-8-yl.
  • Embodiment 37 The compound of embodiment 1 , 2, or 3, wherein Ring B comprises optionally substituted 2,3,4, 5- tetra hydro- 1 H-azepino[2,3-b]quinolin-9-yl.
  • Embodiment 38 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 37, wherein X is -CH 2 -.
  • Embodiment 39 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 37, wherein X is -0-.
  • Embodiment 40 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, or 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, or 37, wherein X is -CF 2 -.
  • Embodiment 41 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -CH2-CH2-.
  • Embodiment 42 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -CH2-CH2-CH2-
  • Embodiment 43 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -CH2O-.
  • Embodiment 44 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein L is -O-CH2-.
  • Embodiment 45 A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is optionally substituted (1S,2R,3S,5R)-3-(2-(2,3-dihydro-1 H-pyrrolo[2,3-b]quinolin-7- yl)ethyl)-5-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(2,3-dihydroimidazo[1 ,2-c]quinazolin-8-yl)ethyl)-5-(7H-pyrrolo[2,3- d]pyrimidin-7-yl)cyclopentane-1 ,2-diol, optionally substituted (1S,2R,3S,5R)-3-(2-(imidazo[1 ,2- c]quinazolin-8-yl)ethyl)-5-(
  • Embodiment 46 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
  • Embodiment 47 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
  • Embodiment 48 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14,
  • Embodiment 49 The compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, or 28, wherein each substituent, if present, of Ring A, Ring B, and L, has a molecular weight of 15 mg/ml_ to 200 mg/mL.
  • Embodiment 50 A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is:
  • Embodiment 51 A method of treating cancer, infectious diseases, and other PRMT5- related diseases or disorders comprising administering a compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • Embodiment 52 Use of a compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer, infectious diseases, and other PRMT5-related diseases or disorders.
  • Embodiment 53 A pharmaceutical composition comprising a therapeutically effective amount of a compound of embodiment 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, or 30, or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier.
  • 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.
  • For examples in Formula 1-3 and A1 wherein there is a substituent at any position of any of the structures, those skilled in the art will recognize that 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
  • mefa-chloroperoxybenzoic acid m-CPBA (or mCPBA)
  • DIPEA Diisopropylethylamine
  • DIEA Diisopropylethylamine
  • iP ⁇ Net Diisopropylethylamine
  • Lithium hexamethyldisilazide LiHMDS Methansulfonyl chloride: MeSC>2CI
  • Triethylamine Et 3 N or TEA
  • Trifluoroacetic acid TFA Trifluoromethanesulfonic anhydride: Tf20
  • 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 CDCh solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm for the proton and 77.00 ppm for carbon), CD3OD (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 1 Synthesis of (3aR,6R,6aR)-2,2-dimethyl-6-vinyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4- one
  • step 6 compound 2-1 was prepared from compound 1-5 using intermediate 15 as the coupling partner.
  • LC-MS: m/e 619 [M+H] + .
  • step 7 compound 2-3 was prepared from compound 2-2.
  • LC-MS : m/e 459 [M+H] + .
  • Step 5 [102] To a solution of 33.1 g (92.7 mmol) of bromo(methyl)triphenyl-lambda5-phosphane in 200 mL of THF was added 85 ml. (85.0 mmol) of 1 M t-BuOK solution in THF. Then the mixture was stirred at O °C for 1 h, a solution of 10.0 g (30.9 mmol) of compound 3-4 in 10 mL of THF was introduced. The mixture was stirred at 0 °C for additional 1 h and then quenched by addition of 300 mL of saturated NH CI solution.
  • step 3 compound 33 was converted to intermediate rac-34.
  • LC-MS: m/e 279 [M+H] + .
  • step 1 compound 35 was prepared from m-bromoaniline similarly.
  • LC-MS: m/e 290 [M+H] + .
  • step 2 compound 36 was prepared from compound 35 similarly.
  • LC-MS: m/e 417 [M+FI] + .
  • step 3 compound 37 was prepared from compound 36 similarly.
  • LC-MS: m/e 445 [M+H] + .
  • step 1 step 2
  • Step 3 [186] To a stirred solution of 490 mg (1.63 mmol) of compound 84 in 10 mL of ethyl alcohol were added 326 mg (6.52 mmol) of hydrazine hydrate dropwise at RT. The mixture was stirred at 60 °C overnight under nitrogen atmosphere. The mixture was filtered; the filter cake was washed with three 20 mL portions of EtOH and dried to give intermediate 85.
  • LC-MS: m/e 264 [M+H] + .
  • Step 1 [191] Following the procedure described in Scheme 15, step 2, compound 90 was prepared from 5-aminovaleric acid and phthalic anhydride.
  • LC-MS: m/e 248 [M+H] + .
  • step 3 compound 91 was prepared from compound 90.
  • LC-MS: m/e 401 [M+H] + .
  • step 2 compound 92 was prepared from compound 91.
  • LC-MS: m/e 429 [M+H] + .
  • step 3 intermediate 93 was prepared from compound 92.
  • LC-MS: m/e 263 [M+H] + .
  • step 1 compound 94 was prepared from compound 6-methylpiperidin-2-one.
  • LC-MS: m/e 132 [M+H] + .
  • step 3 compound 96 was prepared from compound 95.
  • LC-MS: m/e 415 [M+H] + .
  • step 3 compound 97 was prepared from compound 96.
  • LC-MS: m/e 443 [M+H] + .
  • step 1 compound 99 was prepared from delta-valerolactone and m-bromoaniline.
  • LC-MS: m/e 272 [M+H] + .
  • Step 3 [202] Following the procedure described in Scheme 16, step 3, compound 101 was prepared from compound 100.
  • LC-MS: m/e 373 [M+H] + .
  • step 5 compound 103 was prepared from compound 102.
  • LC-MS: m/e 311 [M+FI] + .
  • step 2 compound 104 was prepared from compound 103.
  • LC-MS: m/e 441 [M+FI] + .
  • step 3 compound 105 was prepared from compound 104.
  • LC-MS: m/e 469 [M+FI] + .
  • step 4 intermediate 106 was prepared from compound 105.
  • LC-MS: m/e 303 [M+H] + .
  • step 2 compound 112 was prepared from aminocaproic acid and phthalic anhydride.
  • LC-MS: m/e 262 [M+H] + .
  • step 3 compound 113 was prepared from compound 112.
  • LC-MS: m/e 463 [M+FI] + .
  • step 3 compound 114 was prepared from compound 113.
  • LC-MS: m/e 491 [M+FI] + .
  • step 3 compound 115 was treated with hydrazine in butanol to give compound 114.
  • LC-MS: m/e 361 [M+H] + .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Biotechnology (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

La présente invention concerne de nouveaux inhibiteurs hétérocycliques de PRMT5 et leurs procédés de préparation. L'invention concerne également des compositions pharmaceutiques comprenant lesdits inhibiteurs de PRMT5 et des méthodes d'utilisation de celles-ci pour le traitement du cancer, de maladies infectieuses et d'autres troubles associés à PRMT5.
PCT/US2020/034711 2017-12-05 2020-05-27 Composés hétérocycliques en tant qu'inhibiteurs de prmt5 WO2020243178A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
AU2020283505A AU2020283505A1 (en) 2019-05-30 2020-05-27 Heterocyclic compounds as PRMT5 inhibitors
JP2021570954A JP2022534998A (ja) 2019-05-30 2020-05-27 Ｐｒｍｔ５阻害剤としての複素環式化合物
CA3141855A CA3141855A1 (fr) 2019-05-30 2020-05-27 Composes heterocycliques en tant qu'inhibiteurs de prmt5
KR1020217043087A KR20220016194A (ko) 2019-05-30 2020-05-27 Prmt5 억제제로서의 헤테로시클릭 화합물
EP20814821.3A EP3976038A4 (fr) 2019-05-30 2020-05-27 Composés hétérocycliques en tant qu'inhibiteurs de prmt5
CN202080052198.1A CN114126614A (zh) 2019-05-30 2020-05-27 作为prmt5抑制剂的杂环化合物
US17/532,964 US20220089612A1 (en) 2017-12-05 2021-11-22 Heterocyclic compounds as prmt5 inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201962854435P 2019-05-30 2019-05-30
US62/854,435 2019-05-30
US202062966337P 2020-01-27 2020-01-27
US62/966,337 2020-01-27

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/058721 Continuation-In-Part WO2019112719A1 (fr) 2017-12-05 2018-11-01 Composés hétérocycliques en tant qu'inhibiteurs de prmt5

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US17/532,964 Continuation US20220089612A1 (en) 2017-12-05 2021-11-22 Heterocyclic compounds as prmt5 inhibitors

Publications (1)

Publication Number Publication Date
WO2020243178A1 true WO2020243178A1 (fr) 2020-12-03

Family

ID=73553050

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2020/034711 WO2020243178A1 (fr) 2017-12-05 2020-05-27 Composés hétérocycliques en tant qu'inhibiteurs de prmt5

Country Status (7)

Country Link
EP (1) EP3976038A4 (fr)
JP (1) JP2022534998A (fr)
KR (1) KR20220016194A (fr)
CN (1) CN114126614A (fr)
AU (1) AU2020283505A1 (fr)
CA (1) CA3141855A1 (fr)
WO (1) WO2020243178A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024032572A1 (fr) * 2022-08-09 2024-02-15 上海湃隆生物科技有限公司 Nouvel inhibiteur de prmt5 et son utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180243328A1 (en) * 2015-08-26 2018-08-30 Janssen Pharmaceutica Nv Novel 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as prmt5 inhibitors
US20190048014A1 (en) * 2017-08-09 2019-02-14 Prelude Therapeutics, Incorporated Selective Inhibitors Of Protein Arginine Methyltransferase 5 (PRMT5)
WO2019112719A1 (fr) * 2017-12-05 2019-06-13 Angex Pharmaceutical, Inc. Composés hétérocycliques en tant qu'inhibiteurs de prmt5
WO2019116302A1 (fr) * 2017-12-13 2019-06-20 Lupin Limited Composés hétérocycliques bicycliques substitués utilisés en tant qu'inhibiteurs de prmt5
WO2020033288A1 (fr) * 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2969295A1 (fr) * 2016-06-06 2017-12-06 Pfizer Inc. Derives de carbonucleosides substitues et leur utilisation comme inhibiteur de prmt5
WO2018065365A1 (fr) * 2016-10-03 2018-04-12 Janssen Pharmaceutica Nv Nouveaux analogues de carbanucléoside substitués par un système cyclique, monocyclique et bicyclique destinés à être utilisés en tant qu'inhibiteurs de prmt5
US11220524B2 (en) * 2017-02-20 2022-01-11 Prelude Therapeutics Incorporated Selective inhibitors of protein arginine methyltransferase 5 (PRMT5)

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180243328A1 (en) * 2015-08-26 2018-08-30 Janssen Pharmaceutica Nv Novel 6-6 bicyclic aromatic ring substituted nucleoside analogues for use as prmt5 inhibitors
US20190048014A1 (en) * 2017-08-09 2019-02-14 Prelude Therapeutics, Incorporated Selective Inhibitors Of Protein Arginine Methyltransferase 5 (PRMT5)
WO2019112719A1 (fr) * 2017-12-05 2019-06-13 Angex Pharmaceutical, Inc. Composés hétérocycliques en tant qu'inhibiteurs de prmt5
WO2019116302A1 (fr) * 2017-12-13 2019-06-20 Lupin Limited Composés hétérocycliques bicycliques substitués utilisés en tant qu'inhibiteurs de prmt5
WO2020033288A1 (fr) * 2018-08-07 2020-02-13 Merck Sharp & Dohme Corp. Inhibiteurs de prmt5

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM COMPOUND U.S. National Library of Medicine; 22 April 2017 (2017-04-22), ANONYMOUS: "Compound Summary for CID 126636995", XP055763231, retrieved from NCBI Database accession no. CID 126636995 *
DATABASE PUBCHEM COMPOUND U.S. National Library of Medicine; 22 April 2017 (2017-04-22), ANONYMOUS: "Compound Summary for CID 126636998", XP055763218, retrieved from NCBI Database accession no. CID 126636998 *
DATABASE PUBCHEM COMPOUND U.S. National Library of Medicine; 22 April 2017 (2017-04-22), ANONYMOUS: "Compound Summary for CID 126637397", XP055763222, retrieved from NCBI Database accession no. CID 126637397 *
DATABASE PUBCHEM COMPOUND U.S. National Library of Medicine; 22 April 2017 (2017-04-22), ANONYMOUS: "Compound Summary for CID 126638624", XP055763226, retrieved from NCBI Database accession no. CID 126638624 *
See also references of EP3976038A4 *

Also Published As

Publication number Publication date
EP3976038A1 (fr) 2022-04-06
AU2020283505A1 (en) 2021-12-23
EP3976038A4 (fr) 2023-07-12
KR20220016194A (ko) 2022-02-08
CA3141855A1 (fr) 2020-12-03
JP2022534998A (ja) 2022-08-04
CN114126614A (zh) 2022-03-01

Similar Documents

Publication Publication Date Title
AU2018364938B2 (en) Macrocyclic compounds as TRK kinase inhibitors and uses thereof
AU2016203348C1 (en) Macrocyclic compounds as trk kinase inhibitors
AU2018381004B2 (en) Heterocyclic compounds as PRMT5 inhibitors
JP6204568B2 (ja) タンパク質キナーゼ阻害剤としての縮合複素環化合物
JP5759471B2 (ja) Ｊａｋ３キナーゼ阻害剤としての窒素含有ヘテロアリール誘導体
BR0308243B1 (pt) Derivados de purina como inibidores de quinase, seu uso para tratar diabetes e doença de alzheimer, para estimular deposição óssea e inibir gsk-3, bem como formulação farmacêutica compreendendo os referidos derivados
KR20180003552A (ko) Lsd1 저해제로서 헤테로사이클릭 화합물
CA3224284A1 (fr) Inhibiteur de kras g12d et son utilisation
RU2579513C2 (ru) Ингибиторы активности акт
JP2023527487A (ja) Ｅｎｌ／ａｆ９ ｙｅａｔｓの阻害剤
WO2010092489A1 (fr) Dérivés d'azaindoles comme inhibiteurs des protéines kinases abl et src
WO2020243178A1 (fr) Composés hétérocycliques en tant qu'inhibiteurs de prmt5
AU2021373162A1 (en) Pyrazolopyridazinone compound, and pharmaceutical composition and use thereof
CA3083959C (fr) Inhibiteurs d'irak4 et leurs utilisations
WO2022127755A1 (fr) Composés utilisés en tant qu'inhibiteurs de la caséine kinase
AU2022240935A1 (en) New thiazolopyrimidinone derivatives
WO2021206955A1 (fr) Composés macrocycliques en tant qu'inhibiteurs de kinases et leurs utilisations
US20220089612A1 (en) Heterocyclic compounds as prmt5 inhibitors
WO2024067694A1 (fr) Composé hétérocyclique contenant de l'azote et son utilisation pharmaceutique

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20814821

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3141855

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021570954

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020283505

Country of ref document: AU

Date of ref document: 20200527

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20217043087

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020814821

Country of ref document: EP

Effective date: 20220103