WO2018165112A1 - Composé bicyclique et son utilisation pour inhiber l'histone méthyltransférase - Google Patents

Composé bicyclique et son utilisation pour inhiber l'histone méthyltransférase Download PDF

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Publication number
WO2018165112A1
WO2018165112A1 PCT/US2018/021079 US2018021079W WO2018165112A1 WO 2018165112 A1 WO2018165112 A1 WO 2018165112A1 US 2018021079 W US2018021079 W US 2018021079W WO 2018165112 A1 WO2018165112 A1 WO 2018165112A1
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Prior art keywords
chloro
imidazo
pyridin
dimethoxyphenyl
methyl
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PCT/US2018/021079
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English (en)
Inventor
Srinivas RAVULA
Vijayasaradhi Sivalenka
Manohar MANTIPALLY
Praveen PATNAIK
Praveen DUPATI
Anjan Chakrabarti
Yusuke Nakamura
Yo Matsuo
Takashi Miyamoto
Yasuhide Okamoto
Zhiyong Duan
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Oncotherapy Science, Inc.
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Publication of WO2018165112A1 publication Critical patent/WO2018165112A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • 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 invention relates to a compound having an inhibitory activity against SUV39H21 , a method for the preparation thereof and a pharmaceutical composition containing the compound as an active ingredient.
  • the present invention relates to a method for treatment or prevention of a disease that involves overexpression of a histone methyitransferase such as SUV39H2.
  • the nucleosome the basic unit of D A packaging in eukaryotes that consists of a
  • Non-Patent Document 1 All four core histones (H3, H4, H2A and H2B) possess unstructured N-terminal tails and these N-termini of histones are particularly subjected to a diverse array of post-transiational modifications: acetyiation, methylation, phosphorylation, ubiquitination, SUMQyiation and ADP-ribosylation [Non-Patent Document 2].
  • Non-Patent Documents 3 and 4 These histone modifications cause dynamic changes to the chromatin structure and thereby impinge on transcriptional regulation, DNA replication, DNA repair, and alternative splicing [Non-Patent Documents 3 and 4]. Among these epi genetic marks on histones, the methylation process is particularly crucial for transcriptional regulation [Non-Patent Document 5] . Five lysine residues (H3K4, H3K9, H3K27, H3K36 and
  • H4K20 are located in the N-terminal tails and are representative lysines that can become mono-, di-, or trimethylated.
  • methylation marks on H3K4 and H3K36 are associated with the induction of active transcription [Non-Patent Document 6].
  • methylation of histone H3 at lysine 9 (H3K9) is one of the most abundant and stable histone modifications, and is involved in both gene repression and heterochromatin formation.
  • H3K9 can be mono-, di- or trimethylated on H3K9, whereas silent euchromatin regions are enriched for mono- and dimethylated H3K9 [Non-Patent Document 17].
  • heterochromatic regions are highly trimethylated on H3K9, whereas silent Vietnamese regions are enriched for mono- and dimethylated H3K9 [Non-Patent Document 17] .
  • H3K9 methylation has been linked to de novo gene silencing and DNA methylation, and it is inherited after mitosis in a manner coupled to DNA methylation ,
  • Non-Patent Document 7, 8, 9, 10, and 11 SMYD3, P MTL PRMT6, SUV420H1 and SUV420H2 have been shown to stimulate the proliferation of cells through its enzymatic activity [Patent Document L 8, 9, 12, 13, 14, and 18] .
  • SUV39H2 also known as KMT1B [Non-Patent Document 15] is a SET-domain containing histone methyltransferase and is known to methyiate the H3K9 lysine residue.
  • Suv39h2 the murine homologue of human SUV39H2 has been isolated and characterized as the second murine Suv39h gene, and demonstrated to share 59% identity with Suv39hl [Non-Patent Document 16] .
  • Hie expression of Suv39h2 is restricted to adult testis, and immunolocalization of endogenous Suv39h2 protein reveals enriched distributions at heterochromatin during the first meiotic prophase and in the early stages of sperminogenesis.
  • Suv39h2 specifically accumulates within the chromatin of the silenced sex chromosomes present in the XY body, hi addition, the histone
  • the present inventors have endeavored to develop an effective inhibitor of a histone methy ⁇ transferase, particiilarly SUV39H2 and have found that a compound can selectively inhibit the activity of SUV39H2.
  • R 1 and R 2 are independently selected from the group consisting of a hal ogen atom, hydroxy, Ci-Ce alkyS, and Ci-Ce alkoxy;
  • R 3 is independently selected from the group consisting of a halogen atom, cyano, nitro, hydroxy, carboxy, Ci-Ce alkyl, C1-C5 alkoxy, (Ci-Ce alkoxy )carbonyl, Ci-Ce alkylthio, Ci-Ce aikylsuifmyl, and Ci -Ce alkyl sulfonyl;
  • n is an integer selected from 0 to 3:
  • R 4 is selected from the group consisting of a hydrogen atom, and a halogen atom:
  • R 5 is independently selected from the group consisting of a halogen atom, Ci-Ce a!kyl, and Ci-Ce alkoxy;
  • n an integer selected from 0 to 3;
  • X and Y are independently selected from a direct bond, -CH2-, and -CH2CH2-;
  • R 6 is selected from the group consisting of Ci-Ce aikyi substituted with one or more substituents selected from Ra, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rb, CS-CJO aryl optionally substituted with one or more substituents selected from Rb, 5- to 10-membered heteroaryl optionally substituted with one or more substituents selected from Rb, 3- to 12-membered non-aromatic heterocyclyl optionally substituted with one or more substituents selected from Rb, (Ci-Ce
  • R 7 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra:
  • Q is selected from Ci-Ce alkylene
  • R 10 is independently selected from the group consisting of a halogen atom, and Ci-
  • q is an integer selected from 0 to 4.
  • Ra is independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkoxy, cyano, (C i-Ce alkoxy jearbonyl, carboxy, (Ci-Ce alkoxy)carbonylamino, (Ci- Cf, alkyljcarbonylamino, amino, Ci-Ce alk lammo, di(C; -C6 alkyl)amino, aminocarbonyl, (Ci -Ce alkyl)aminocarbonyl, di(Ci-Ce alkyl)aminocarbonyl, Ci-Ce alkylsulfonylamino, C.3- Cio cyeloalkyisulfonylamino, C3-G0 cycloalkyl optionally substituted with one or more substituents selected from Rc, C3-C10 eycloalkenyl optionally substituted with one or more substituents selected from Rc, Ce-Cio
  • Rb is independently selected from the group consisting of a halogen atom, hydroxy , Ci-Cr, alkyl optionally substituted with one or more substitutents selected from Ra, Ci-Ce alkoxy optionaliy substituted with one or more substitutents selected from Ra, cyano, (Ci- Ce alkoxy)carbonyl, carboxy, -NR 2 l R 22 , -CONR 23 R 24 , diiCi-Ce alkyl)phosphono, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10- membered lieteroaryi optionally substituted with one or more substituents selected from Rc, and 3- to 12-membered non-aromatic heterocyciyi optionaliy substituted with one or more substituents selected from Re;
  • Rc is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alky] optionally substituted with one or more halogen atoms, Ci-Ce alkoxy optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci -Ce alkylarnino, di(Ci-C6 alkyl)amino, (Ci-Ce aikyi)carbonyl, (Ci-Ce alkoxy)carbonyl, Ci-Ce alkylsulfonyl, C3-G0 cycloalkylsulfonyl, CT-CM aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Re, 3 ⁇ to 12-membered non-aromatic heterocycly
  • Rd is independently selected from the group consisting of nitro, hydroxy, Ci-Ce. alkyi optionally subsituted with one or more halogen atoms, Ci -Ce alkoxy optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylarnino, di(Ci-Ce alkyijammo, Ci-Ce alkylearbonyl, (Ci-Ce alkoxy)carbonyl, Ci-Ce alkylsulfonyl, CJ ⁇ CS cycloalkyisulfonyl, C7-C14 aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, Cs-Cs cycloalkyl optionally substituted with one or more substituents selected from Re, 3- to 12-membered non-aromatic heterocyclyl optional
  • Re is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyi optionally subsituted with one or more halogen atoms, a halogen atom, ammo, cyano, Ci-Ce alkylarnino, di ⁇ Ci-Ce alkyl)amino, Ci-Ce alkylearbonyl, (Ci-Ce alkoxyjcarbonyl, Ci- Ce alkylsulfonyl, and C3-C8 cycloalkyisulfonyl ;
  • R 21 is selected from the group consisting of a hydrogen atom, Ci -Ce alkyi optionally substituted with one or more substituents selected from Ra, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 4- to 12-membered heterocyciyl optionally substituted with one or more substituents selected from Rc, 5- to 10- membered lieteroaryl optionally substiMed with one or more substituents selected from Rc, (Ci-Ce alkoxy)carbonyl optionally substituted with one or more substituents selected from Ra, (Ci-Cc alkyl)carbonyl optionally substituted with one or more substituents selected from Ra, (C3-C 10 cycIoaIkyl)carbonyl, (Ce-Cio aryl)carbonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membered non-aromatic
  • heterocyclyl)carbonyl optionally substituted with one or more substituents selected from Rc, (5- to 10-nienibcred heteroaiyl)carboiiyl optionally substituted with one or more
  • substituents selected from Rc aminocarbonyl , (Ci-Ce alkyl ⁇ aminocarbonyi optionally substituted with one or more substituents selected from Ra, di(Ci-C6 alkyl)aminocarbonyl optionally substituted with one or more substituents selected from Ra, Ci-Ce alkylsulfonyi optionally substituted with one or more halogen atoms, C7-C14 aralkylsultbnyl, C3-C10 cycloalkyisulfonyl, aminosulfonyl, Ci-Ce alkyiaminosuifbnyi, di(CVC6 alkyl)aminosuifonyl, and di(Ci-Cb aikyl)phosphono;
  • R 22 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra;
  • R 2 - 1 is selected from the group consisting of a hydrogen atom, Ci-Cr, alkyl optionally substituted with one or more substituents selected from Ra, [(Ci-Ce
  • R 24 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra.
  • R 6 is selected from the group consisting of pyrimidyl, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, piperidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy )carbonyl group, pyrrolidyl optionally substituted with a Ci- Ce alkyl group or a (Ci-Ce alkoxy)carbonyl group, C3-C7 cycloalkyl optionally substituted with a di(Ci-C& alkyl)amino groupor a Ci-Ce alkyl group, tetrahydrofuryl, tetrahydropyranyl, phenyl optionally substituted with one substituent selected from Rb, a group -Cft-Ra, a group -CHaCH -Ra and
  • Ra is independently selected from the group consisting of hydroxy, Ci -Ce. alkoxy, C3-C7 cycloalkyl optionally substituted with a di(G-Gs alkyl)amino group, phenyl optionally substituted with one or more substituents selected from Rd, pyrrolidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy)carbonyl group, piperidyl optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy )carbonyl group, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, thiazolyi, thienyl, pyrimidyl optinally substituted with a di(Ci-Ce alkyl)amino group, and
  • Rb and Rd are independently selected from the group consisting of a halogen atom, methyl, cyano dimethy!audino, methoxy, nitro, hydroxy, and trifluoromethyl.
  • Q is selected from the group consisting of -CH2-, -CH(CH3)-, -CH(Q-bCH3)-, CH2CH2-, -CH(CH3)CH2-, and -CH?.CH(CH3)-; - R 1 , R 2 , R ⁇ R , R 5 , R 6 , R 7 , X, Y, m and n are as defined in any one of [1] to [5J .
  • R 1 and R 2 are independently selected from the group consisting of Ci-Ce alkoxy,
  • p is an interger selected from 0 and 1 :
  • R 3 is selected from the group consisting of a harogen atom
  • R 6 and 7 are as defined m any one of [1] to [6].
  • a phamiaceutical composition comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [10].
  • R 1 and R 2 are independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkyl, and Ci-Ce alkoxy;
  • R 3 is independently selected from the group consisting of a halogen atom, cyano, nitro, hydroxy, carboxy, Ci-Ce alkyl, Ci-Ce alkoxy, (Ci-Ce. alkoxy)carbonyl, Ci-Ce aikylthio, Ci-Ce aikylsuifinyl, and Ci-Ce alkylsulfonyi;
  • n is an integer selected from 0 to 3;
  • R 4 is selected from the group consisting of a hydrogen atom, and a halogen atom;
  • R 5 is independently selected from the group consisting of a hydrogen atom , a halogen atom, Ci-Ce alkyl, and Ci-Ce alkoxy;
  • n is an integer selected from 0 to 3;
  • p is an integer selected from 0 and 1 ;
  • R 6 is is selected from the group consisting of Ci-Ce alkyl substituted with one or more substituents selected from Ra, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rb, Ce-Cio aryl optionally substituted with one or more substituents selected from Rb, 5- to 10-membered hcteroary! optionally substituted with one or more substituents selected from Rb, 3- to 12-membered non-aromatic heterocyc optionally substituted with one or more substituents selected from Rb, (Ci -Ce
  • R 7 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra; or
  • Ra is independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkoxy, cyano, (Ci-Ce aikoxy)carbonyl, carboxy, (Ci-Gs alkoxy)carbonyl amino, (Ci- Ce alky])carbonylamino, amino, Ci-Ce aJkylamino, diiCi-Ce alky])amino, aminocarbonyl, (Ci-Ce alky])aminocarbonyl, di(Ci-C6 aIkyl)aminocarbonyl, Ci-Ce alkylsulfonylamino, C3- C10 cycloalkylsulfonyiamino, C3-C10 cycloalkyl optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10-membered heteroaiyl optionally
  • Rb is independently selected from the group consisting of a halogen atom, hydroxy, Ci-Ce alkyl optionally substituted with one or more substitutents selected from Ra, Ci -Ce alkoxy optionally substituted with one or more siibstitutents selected from Ra, cyano, (Ci- Cf, alkoxy)carbonyL carboxy, -NR 21 R 22 , -CONR 23 R 24 , di(Ci-C6 alkyl)phosphono, C3-C10 cycloalkyi optionally substituted with one or more substituents selected from Rc, Ce-Cio aryl optionally substituted with one or more substituents selected from Rd, 5- to 10- membered heteroaryl optionally substituted with one or more substituents selected from Rc, and 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Rc;
  • Rc is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyl optionally substituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylamino, di(Ci-C ' 6 alkyi)amino, (Ci-Ce alkyljcarbonyi, (Ci-Ce alkoxy )earbonyi, Ci-Cr, alkyisulfonyl, C3-G0 cycloaikylsulfonyl, C?-C; 4 aralkyl optionally substituted with one or more substituents selected from Re, Ce-Cio aryl optionally substituted with one or more substituents selected from Re, C3-C10 cycloalkyi optionally substituted with one or more substituents selected from Re, 3- to 12-membered non-aromatic heterocyciyl optionally substituted with one or more substituents selected from Re, 5- to 10-
  • Rd is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyl optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, Ci-Ce alkylamino, i ⁇ ( ' :-( ' .-.
  • Re is independently selected from the group consisting of nitro, hydroxy, Ci-Ce alkyl optionally subsituted with one or more halogen atoms, a halogen atom, amino, cyano, C1-C5 alkylamino, di(C] -Ce alkyl)amino, Ci-Ce aikylcarbonyl, (Ci-Ce alkoxy)carbony3, Ci- Ce alkylsulfonyl, and Cs-Cs cycloalkylsulfonyl;
  • R 21 is selected from the group consisting of a hy drogen atom, Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra, Cs-Cio aryl optionally substituted with one or more substituents selected from Rd, 4- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from Re, 5- to 10- membered heteroaryl optionally substituted with one or more substituents selected from Rc, (Ci-Ce aIkoxy)carbonyl optionally substituted with one or more substituents selected from Ra, (Ci -Ce alkyl)carbonyl optionally substituted with one or more substitiients selected from Ra, (C. -Cso cycloalkyl)carbonyl, (Ce-Cio aryl)carbonyl optionally substituted with one or more substituents selected from Rd, (3- to 12-membered non-aromatic
  • heterocyci.yl)carbonyl optionally substituted with one or more substituents selected from Rc, (5- to 10-membered heteroaryl)carbonyi optionally substituted with one or more
  • substituents selected from Rc aminocarbonyl, (C1-C0 alkyljaminocarbonyl optionally substituted with one or more substituents selected from Ra, di(Ci-Ce alkyl)aminocarbonyl optionally substituted with one or more substituents selected from Ra, Ci-Ce alkylsulfonyl optionally substituted with one or more halogen atoms, C7-C14 aralkylsulfonyl, C3-G0 cycloalkylsulfonyl, aminosulfonyl, Ci-Ce alkylaminosulfonyl, diCG-Ce alkyl)aminosuifonyl, and di(Ci-C& alkyl)phosphono;
  • R 22 is selected from the group consisting of a hydrogen atom, and Ci-Gs alkyl optionally substituted with one or more substituents selected from Ra;
  • R 23 is selected from the group consisting of a hydrogen atom, Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra, [(Ci -Ce
  • R 24 is selected from the group consisting of a hydrogen atom, and Ci-Ce alkyl optionally substituted with one or more substituents selected from Ra.
  • R 1 and R 2 are independently selected from the group consisting of Ci-Ce alkoxy,
  • R 3 is selected from the group consisting of a harogen atom
  • R 6 , R' and p are as defined in [1 ] .
  • R 6 is selected from the group consisting of pyrimidyl, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, piperidyl optionally substituted with a Ci-Ce alkyi group or a (Ci-Ce alkoxy )earbonyl group, pyrrolidyl optionally substituted with a Ci-C-6 aJkyl group or a (Ci-Ce alkoxy)carbony1 group, C3-C?
  • Ra is independently selected from the group consisting of hydroxy, Ci-Ce alkoxy, C3-C7 cycloalkyl optionally substituted with a difCi-Ce alkyl)amino group, phenyl optionally substituted with one or more substituents selected from Rd, pyrrolidyl optionally substituted with a Ci-Ce aikyl group or a (Ci-Ce alkoxy)carbonyl group, pipcridyi optionally substituted with a Ci-Ce alkyl group or a (Ci-Ce alkoxy )carbonyl group, pyridyl optionally substituted with a halogen atom or a Ci-Ce alkoxy group, and thiazoiyl.
  • Rb and Rd are independently selected from the group consisting of a halogen atom, methyl, cyano dimetliylammo, metlioxy, nitro, hydroxy, and trifluoromethyl
  • N-Ben3 ⁇ 4 j 3-l-(l -(2-(5-cUoro-2,4-diine1iioxyphenyl)imidtizo[i ,2-a]pyridin-7- yl)piperidin-4-y 3)metlianamine ;
  • a phannaceutical composition comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [10].
  • a pharmaceutical composition according to [12], wherein the cancer is selected from the group consisting of lung cancer, cervical cancer, bladder cancer, esophageal cancer, osteosarcoma, prostate cancer and soft tissue tumor.
  • examples of the "Ci-Ce alkyl” and the “Ci-Ce alkyl portion” include methyl, ethyl, propyl, isopropyS, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1 -meihylbutyl, l ⁇ ethy]propy1, 2-methylbuiyi, isopenty], tert-pentyl, 1 ,2- dimethylpropyl, neopentyl, hexyl, i-methylpentyl, l-ethylbutyl, 2-methylpentyl, 3- methyipentyl, 4-methylpentyl, isohexyi, 1 , 1-diniethylbutyi, 1 ,2-dimethylbutyl, 1 ,3- dimethylbutyl, 1-isopropylpropyl, 1 -ethyl- 1 -me
  • Ci-Ce alkyl portion in each group has the same definition as the aforementioned "Ci-Ce alkyl portion" unless otherwise noted. In a case that a group contains plural Ci-Ce alkyl portions, the Ci-Ce alkyl portions may be same or different.
  • Ci-Ce alkoxy examples include methoxy, ethoxy, propoxy, isopropoxy, isobutyloxy, tert-butyloxy, butoxy, pentyloxy, and hexyloxy, but are not limited thereto.
  • Specific examples of "(Ci-Ce aikoxy)carbonyi” include metlioxycarbonyl, ethoxycarbonyl, propoxycaibonyl, isopropoxycarbonyl,
  • Specific examples of "(Ci-Ce alkyljearbonyf include methylcarbonyl (i.e . acetyl), ethylcarbonyl, propylearbonyl, isopropylcarbonyl, isobutyicarbonyl, tert- butylcarbonyl , butylearbonyl, pentylcarbonyl, and hexylcarbonyl, but are not limited thereto.
  • Ci-Ce alkylamino include methylamino, ethylamino, propylamino, isopropylaroino, butyl amino, isobutylamino, sec-butylamino, and tert- butyiamino, pentylamino, but are not limited thereto.
  • alkyl portions of "di(C i-Ce alkyl iamino" may be same or different.
  • Specific examples of “di(Ci-Ce alkyl Iamino” include dimethylaniino, diethylamino, dipropylainino, diisopropylamino, dibutylammo, diisobutylammo, di(see-butyi)amino, di(tert-butyl)ammo, dipentyl amino, ethyl ⁇ methyi)ammo, propyl (methyi)amino, isopropyl(methyl)amino, butyl(methyi)a.mmo, isobutyl(methyl)amino, sec-butyl(roethyl)amino, tert- butyl(memyl)amino, and pentyl(methyl)ammo, but are not limited thereto.
  • a halogen atom include a fluorine, a chlorine, a bromine, and an iodine atoms.
  • C3-O0 cyeloalkyr refers to a saturated monocyclic hydrocarbon group having three to ten carbon atoms, and a bridged cyclic hydrocarbon group having four to ten carbon atoms which is formed when two or more saturated monocyclic hydrocarbons share two or more carbon atoms.
  • C3-C10 cycloalkyl also encompasses a cycloalkyl group condensed with an aromatic or non-aromatic carbocyclic ring to form a bi cycl c group.
  • C.3-C10 cycloalkyl include saturated monocyclic hydrocarbon groups such as cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, and bridged cyclic hydrocarbon groups such as adamantyl, but are not limited thereto.
  • C3-C10 cycloalkoxy examples include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyioxy, and bridged cyclic hydrocarbon groups such as adamantyioxy, but are not limited thereto.
  • Ce-Cio aryl refers to an aromatic carbocyclic group having six to ten carbon atoms, and encompasses an aromatic carhoeyciic group condensed with an aromatsc or non-aromatic carbocyclic ring to form a bicyclic group. Specific examples include phenyl 1-naphthyl, 2-naphthyl, and 2,3-dihydro-l H-indenyl, but are not limited thereto.
  • C7-C1 aralkyl refers to an alkyl group substituted with an aryl group that has 7 to 14 carbon atoms. Specific examples include benzyl, 2-phenylethyl, 1- phenylethyl, naphtha- 1-ylmethyl, naphtha-2-ylmethyl, and 2,3-dihydro-lH-inden-4- ylmethyl, but are not limited thereto.
  • C7-C 1 4 aralkyl portion of "C7-C14 araSkylsuSfonyl” and the like mean the same as described above.
  • examples of "C7-C14 aralkyl sulfonyl” include benzyl sulfonyl, but are not limited thereto.
  • the term "5- to 10-membered heteroaryl” refers to an aromatic heterocyclic group having one or more heteroatoms, preferably one to three heteroatoms, selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • the term "5- to 10-membcred heteroaryl” encompasses an aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicyclic group, and also encompasses an aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bicyclic group.
  • thienyl, pyrrolyl, imidazolyl, isoxazoiyl, pyridyl, pyrimidinyl, pyrazolyi, lH-indazolyl, benzimidazolyl, j l,2,4]triazolo l,5-a]pyridyl, or pyrrolo[2,3-b]pyridyl is preferred.
  • 3- to 12-membered non-aromatic heterocyciyl refers to a non-aromatic heterocyclic group having one or more heteroatoms, preferably one to three heteroatoms, selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • Hie term "3- to 12-membered non-aromatic heterocyciyl” encompasses a non-aromatic heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicychc group, and also encompasses a non-aromatic carbocyclic group condensed with an aromatic or non-aromatic heterocyclic ring to form a bieyclic group.
  • azindinyl azetidinyS, pyrrolidinyl, piperidyl (including piperidino), azepanyl, 1 ,2,5,6-tetrahydropyridyS, 1,2,3,6- tetrahydropyridyl, miidazolidinyl, pyrazolidinyl, piperazinyl, homopiperazmyl, pyrazohnyl, oxiranyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, 5 ,6-dihydro-2H-pyranyl, oxazolidinyl, morphoiiriyi (including morphoiino), tetraliydrothiophenyl, tetrahydro-2H-thiopyra3iyl, thioxazolidinyl, tbiomo ⁇ olinyl, 2H-oxazolyl, 2H-
  • l]octyl, piperidin-4-spiro-3 '-pyrrolidin- 1 -y 1, and isoindoiyl but are not limited thereto.
  • 3- to 12-membered nitrogen-containing heterocyciyi refers to an aromatic or non-aromatic heterocyclic group having one nitrogen atom and one or more additional heteroatoms, preferably one to three heteroatoms, selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom.
  • the term "3- to 12- membered nitrogen -containing heterocyciyi” encompasses a heterocyclic group condensed with an aromatic or non-aromatic carbocyclic ring or an aromatic or non-aromatic heterocyclic ring to form a bicycHc group.
  • niorpholinyi examples include aziridinyl, azetidmyl, pynolyi, pyrrolidinyl, piperidyl (including piperidino), azepanvl, imidazoiyl, pyrazolyl, triazolyl, tetrazolyl, piperazinyl, and niorpholinyi.
  • Ci-Ce alkylene refers to a linear or branched divalent group having 1 to 6 carbon atoms, and includes C1-C4 alkylene and X1-C3 alkylene. Examples thereof include -CH2-, -CH(CH 3 ) ⁇ , -CHiCH CHs)-, -CH2CH2-, -CH(CH 3 ⁇ CH2-, and -CH2CH(C3 ⁇ 4)-
  • Pharmaceutically acceptable salts of compound (1) mean, for example, pharmaceutically acceptable acid-added salts, amino acid-added salts, or such.
  • Specific examples of the pharmaceutically acceptable acid-added salts of compound (I) mclude inorganic acid salts such as hydrochloride, sulfate, and phosphate, organic acid salts such as acetate, maleate, furnarate, citrate, and such, and examples of pharmaceutically acceptable amino acid-added salts include addition salts such as of lysine, glycine, phenylalanine, asparagine acid, or glutamic acid.
  • Pharmaceutically acceptable salts of compound (I) include hydrochloride salt, dihydrochloride salt, and trihydrochloride salt.
  • Examples of diseases involving overexpression of SUV39H2 which may be treated and/or prevented by pharraaceuticai compositions comprising as an active ingredient a compound or a pharmaceutically acceptable salt thereof of the present invention, include cancer, breast cancer, bladder cancer, cervical cancer, cholangiocellular carcmoma, chronic myeloid leukemia (CML), colorectal cancer, endometriosis, esophagus cancer, gastric cancer, liver cancer, non-small cell king cancer (NSCLC), lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma and small cell lung cancer (SCC), but are not limited thereto.
  • CML chronic myeloid leukemia
  • NSCLC non-small cell king cancer
  • SCC small cell lung cancer
  • cancers which may be treated and/or prevented include breast cancer, bladder cancer, cervical cancer, cholangiocellular carcinoma, CML, colorectal cancer, endometriosis, esophagus cancer, gastric cancer, liver cancer, NSCLC, lymphoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal carcinoma and SCC, but are not limited thereto.
  • the examples of cancer includes lung cancer, cervical cancer, bladder cancer, esophageal cancer, osteosarcoma, prostate cancer and soft tissue tumor.
  • Compound (I) includes compounds which may have stereoisomers such as regioisomers, geometrical isomers, optical isomers, and tautomers, and ail possible isomers including them and mixtures thereof are included in the present invention.
  • Compound (I) also mcludes compounds having one or more minor stable isotopes or radio isotopes such as 3 ⁇ 4, 3 H, 1 J C, 14 C, ] 3 N, !8 0 and the like, which can be preprared in line with comventional procedures for preparing a compound with one or more isotopes indicated abo ve .
  • compound (I) and pharmaceutically acceptable salts thereof may exist in a form of solvate with water (hydrate) or various other solvents, and these solvates are also included in the present invention.
  • Compound (1) and pharmaceutically acceptable salts thereof may be administered singly as they are: however, ordinarily, they are desirably provided as various types of pharmaceutical formulations. Such pharmaceutical formulations are used for animals or humans.
  • compositions of the present invention may comprise as an active ingredient compound (I) or a phannaceuticail y acceptable salt thereof alone, or a mixture with any other active ingredients for treatment. Furthermore, these pharmaceutical formulations are produced by any methods well known in the technical field of drug formulation by mixing the active ingredient together with one or more types of
  • pharmaceutically acceptable carriers for example, diluents, solvents, and excipients.
  • the most effective route of administration is used for the treatment, and examples include oral route, or parenteral route such as intravenous route.
  • the form of administration is, for example, tablets and injections.
  • Tablets are appropriate for oral administration and can be produced using excipients such as lactose, disintegrants such as starch, lubncants such as magnesium stearate, and binders such as hydroxypropylcellulose.
  • Injections are appropriate for parenteral administration, and can be produced using, for example, solvents or diluents such as salt solutions, glucose solutions, or a mixture of salt water and glucose solution .
  • the dose of compound (1) or a pharmaceutically acceptable salt thereof, and the number of doses differs depending on tlie forrn of administration, tlie age and body weight of the patient, tlie nature of tlie symptom to be treated or severity, and such, but ordinarily for oral administration, it is 0.01 mg to 1000 nig, preferably in tlie range of 0.05 nig to 100 mg for an adult, and it is administered once to several times a day. In the case of parenteral administration such as intravenous administration, 0.001 mg to 1000 mg, or preferably 0.01 mg to 100 mg is administered to an adult once to several times a day.
  • intermediates and compounds of interest in the following Examples can be isolated and purified by subjecting them to separation and purification methods commonly used in synthetic organic chemistry unless otherwise specified, and examples include filtration, extraction, washing, drying, concentration, reerystaUization, and various types of chromatographies. Alternatively, intermediates can be subjected to the next reaction without purification.
  • the compound of interest can be produced by using the methods for introducing and removing protecting groups commonly used in synthetic organic chemistry (for example, "Protective Groups in Organic Synthesis", T. W. Greene, John Wiley & Sons Inc., 1999). Furthermore, the order of the reaction processes such as substituent introduction can be changed as necessary.
  • the reaction mixture was cooled to room temperature and concentrated under reduced pressure, whereupon the residue was partitioned between EtOAc and saturated aqueous NaHCCb solution (300 mL: 100 mL). The layers were separated and the EtOAc layer was washed with brine ( 100 mL), dried over anhydrous NazSC , filtered and concentrated under reduced pressure to provide the crade product.
  • dimethyipropan-1 -amine 8a was obtained as an off-white solid (18% yield).
  • A-BenzyI- l-(l -(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ I,2-ii]pyridin-7- yl)piperidin-4-yl)meihanamine 8i was prepared in the same manner as A 7 -((l -(2-(5-chloro- 2,4-dimethoxyphenyl)imidazo[ L2 ⁇ ]pyridm-7-j4)piperidin-4-yi)methyl)-2,2- dimetliylpropan- 1 -amine 8a and was obtained as an off-white solid (26% yield).
  • dimechyipropan-1 -amine 8a was obtained as an off-white solid (13% yield).
  • yl)-A-(4-methoxybenzyi)methaiianiine 8o was prepared in the same manner as N-((l -(2-(5- ehloro-2,4 ⁇ dimethoxyphenyl)imidazo[ l,2 ⁇ a]pyridiii-7 ⁇ yl)piperidin ⁇ 4-yl)methyl)-2,2- dimethylpropan- 1 -amine 8a and was obtained as an off-white solid (8% yield).
  • yl)-N-((2-nle1box5 ⁇ ridin ⁇ - ⁇ 4)metlayl)methanamine 8y was prepared in the same manner as 'V ⁇ (( 1 -(2.-(5 -chloro-2,4-dimethoxypheny i)imidazo[ 1 ,2 ⁇ aipyridm ⁇ 7-yl)piperidin-4- yl)methyl)-2,2-dimethylpropan ⁇ l -amine 8a and was obtained as an off-white solid (14% yield).
  • the crude product was suspended in water (200 mL) and saturated aqueous NaHCOs (200 mL) and stirred at room temperature for 1 h.
  • the solid obtained was filtered under vacuum, washed with water and dried under vacuum to obtain /erf-butyl (( 1 -(2-(5-chloro-2,4-dimethoxyphenyl) imidazo[l,2 ⁇ ]pyridin-7-yl)piperidin-4-yl)methyl)carbamate 13 (1 .2 g, 43.7%) as an off- white solid.
  • reaction mixture was quenched with saturated aq-NJHUCl solution and extracted with CH2CJ2 (2 ⁇ 50 ml,).
  • the combined organic layer was dried over anhydrous a?.S04, filtered and concentrated under reduced pressure to obtain J ⁇ (2- ⁇ 5 ⁇ chloro-2,4-dimethoxyphenyl)imidazo l,2- « pyridin-7-yl)piperidine-4-carbakte 14 (300 mg, 76%) as an off-white solid, which was used for next step without further purification.
  • l,2-a]pyndin-7 ⁇ yl)piperidm ⁇ 4- yl)raethyl)cyeSopeiitaaamine 16c was prepared in the same manner as N-(( l-(2-(5-chloro- 2,4-dimethoxyphenyl)imidazo [ 1 ,2-a]pyridin-7-yl)piperidin-4-yl)methyl)cyclobutanaraine 16a and was obtained as an off-white solid (12% yield).
  • A-((l-(2-(5-chloro-2,4-dimethoxyphenyl)imidazo[ l,2- «]pyridin-7-yl)piperidin-4- yl)metliyl)-i-meth ipiperidin-4-arnine 161 was prepared in the same manner as N-(( ⁇ -(2-(5- chloro-2,4 ⁇ dimethoxyphenyl)imidazo[ l,2 ⁇ a]pyridin-7 ⁇ yl)piperidin ⁇ 4- yl)methyl)cyclobutanamine 16a and was obtained as an off-white solid ( 18% yield).
  • yl)-A-(piperidin-4-ylmethyl)me ⁇ hanamine 22g was prepared in the same manner as 1 -(l-(2- (5-chloro-2,4-dimeflioxyphenyi)imidazo[ l,2-o
  • dimethyipropan- 1 -amine 22a was obtained as an off-white solid (19% yield).
  • dimethyipropan-1 -amine 22a was obtained as an off -white solid ( 14% yield).

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Abstract

La présente invention concerne un composé représenté par la formule (I), un procédé pour sa préparation, et une composition pharmaceutique contenant le composé en tant que principe actif pour inhiber l'histone méthyltransférase telle que SUV39H2.
PCT/US2018/021079 2017-03-09 2018-03-06 Composé bicyclique et son utilisation pour inhiber l'histone méthyltransférase WO2018165112A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022040259A1 (fr) * 2020-08-19 2022-02-24 Bristol-Myers Squibb Company Dérivés d'imidazo[1,2-a]pyridine et de [1,2,4]triazolo[1,5-a]pyridine utiles en tant qu'inhibiteurs de tlr9 pour le traitement d'une fibrose

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050049277A1 (en) * 2000-03-31 2005-03-03 Breitenbucher J. Guy Phenyl-substituted imidazopyridines
US7504501B2 (en) * 2003-03-06 2009-03-17 Merial Limited Antiprotozoal imidazopyridine compounds
WO2014177458A1 (fr) * 2013-04-29 2014-11-06 F. Hoffmann-La Roche Ag Dérivés de 2-phényl- ou 2-hétaryl-imidazol[1,2-a]pyridine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050049277A1 (en) * 2000-03-31 2005-03-03 Breitenbucher J. Guy Phenyl-substituted imidazopyridines
US7504501B2 (en) * 2003-03-06 2009-03-17 Merial Limited Antiprotozoal imidazopyridine compounds
WO2014177458A1 (fr) * 2013-04-29 2014-11-06 F. Hoffmann-La Roche Ag Dérivés de 2-phényl- ou 2-hétaryl-imidazol[1,2-a]pyridine

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Title
DATABASE PubChem 12 February 2015 (2015-02-12), Database accession no. 87367073 *
DATABASE PubChem 25 October 2006 (2006-10-25), Database accession no. 10133248 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022040259A1 (fr) * 2020-08-19 2022-02-24 Bristol-Myers Squibb Company Dérivés d'imidazo[1,2-a]pyridine et de [1,2,4]triazolo[1,5-a]pyridine utiles en tant qu'inhibiteurs de tlr9 pour le traitement d'une fibrose

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