WO2024255810A1 - Dérivés polycycliques contenant de la dihydropyrimidine-2, 4 (1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation - Google Patents

Dérivés polycycliques contenant de la dihydropyrimidine-2, 4 (1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation Download PDF

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WO2024255810A1
WO2024255810A1 PCT/CN2024/099076 CN2024099076W WO2024255810A1 WO 2024255810 A1 WO2024255810 A1 WO 2024255810A1 CN 2024099076 W CN2024099076 W CN 2024099076W WO 2024255810 A1 WO2024255810 A1 WO 2024255810A1
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group
cycloalkyl
independently selected
methyl
ring
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PCT/CN2024/099076
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Inventor
Liqiang Fu
Zude QI
Xuemei JIN
Adrian Contreras
Chin-Chun Lu
Yifeng Xia
Gang Lu
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Hangzhou Glubio Pharmaceutical Co Ltd
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Hangzhou Glubio Pharmaceutical Co Ltd
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Priority to KR1020267001182A priority Critical patent/KR20260022448A/ko
Priority to CN202480040029.4A priority patent/CN121794269A/zh
Priority to AU2024302642A priority patent/AU2024302642A1/en
Priority to EP24822758.9A priority patent/EP4727940A1/fr
Publication of WO2024255810A1 publication Critical patent/WO2024255810A1/fr
Priority to PCT/CN2025/099373 priority patent/WO2025256460A1/fr
Priority to MX2025015193A priority patent/MX2025015193A/es
Priority to IL325349A priority patent/IL325349A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present disclosure relates to medicinal chemistry, in particular, dihydropyrimidine-2, 4 (1H, 3H) -dione-containing polycyclic compounds, or pharmaceutically acceptable salts thereof, and compositions thereof which are effective to reduce or modulate widely interspaced zinc finger motifs (WIZ) protein expression levels and/or induce fetal hemoglobin (HbF) expression, and also relates to methods of their preparation and their use in treatment of subjects in need.
  • WIZ widely interspaced zinc finger motifs
  • HbF fetal hemoglobin
  • Sickle cell disease is caused by the formation of a pathological sickle hemoglobin tetramer consisting of two ⁇ -globin chains and two abnormal ⁇ -globin chains (HbS) , in which the glutamic acid residue at position 6 is replaced by valine owing to a single base change, from adenine to thymine, in the ⁇ -globin gene (HBB) (Rees DC et al., Lancet 2010, 376: 2018-2031) .
  • HBB ⁇ -globin gene
  • the G9a methyltransferase is known to regulate HbF production by repressing the transcription of fetal ⁇ -globin genes (Krivega, et al. Blood, 2015) . WIZ was reported to retain histone H3 lysine 9 methyltransferases G9a and GLP on chromatin to direct the deposition of H3K9me1 and H3K9me2, resulting in gene repression (Bian C et al., Elife 2015, 4: e05606) thereby, potentially contributing to the silencing of ⁇ -globin genes.
  • WIZ is a known neosubstrate of several CRBN-based molecular glue degraders including immunomodulatory (IMiD) drugs and CC-122 (Yu HH et al., bioRxiv 2019 (doi: https: //doi. org/10.1101/595389) ; Hagner PR et al., Blood. 2015, 126: 779-789) .
  • IMD immunomodulatory
  • CC-122 Yu HH et al., bioRxiv 2019 (doi: https: //doi. org/10.1101/595389) ; Hagner PR et al., Blood. 2015, 126: 779-789) .
  • Recruitment of WIZ to the Cul4/DDB1/RBX1/CRBN E3 ligase complex by these compounds results in ubiquitination and subsequent proteasomal degradation of WIZ via a mechanism commonly shared among IMiD substrates (Sievers, Q. L. et al. Science 2018, 362, ea
  • the object of the present invention is to provide a new class of compounds which can reduce/modulate WIZ protein expression levels.
  • X 1 and X 2 are each independently selected from the group consisting of a bond, - (CH 2 ) n -, -CH (R 1 ) (CH 2 ) n -, -C (O) -, and -S (O) 2 -;
  • Ring A is independently selected from the group consisting of C 6 -C 10 aryl, monocyclic 5-or 6-membered heteroaryl, bicyclic 9-or 10-membered heteroaryl, and tricyclic 12-, 13-or 14-membered heteroaryl, wherein the heteroaryl has 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N, wherein the aryl, and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 2 ;
  • Ring B is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 3 ;
  • Ring C is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, C 6 -C 10 aryl-fused C 5 -C 10 cycloalkyl, C 6 -C 10 heteroaryl-fused C 5 -C 10 cycloalkyl, C 6 -C 10 aryl-fused 5 to 10-membered heterocyclyl, and C 6 -C 10 heteroaryl-fused 5 to 10-membered heterocyclyl; wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are independently selected from the group consisting of O, S, and N; wherein the C 6 -C 10 aryl-fused C 5 -C 10 cycloalkyl, C 6 -C 10 heteroaryl-fused C 5 -C 10 cycloalkyl, C 6 -C 10 aryl-fused 5 to 10-membered heterocyclyl, and C 6
  • Ring D is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl, wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 5 ;
  • Ring E is independently selected from the group consisting of absence, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl, wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 6 ;
  • n 0, 1, 2 or 3
  • each R 1 is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, and halogen;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • each R 3 and R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkylester, C 1 -C 6 thioalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and 3 to 8-membered heterocyclyl, wherein the cycloalkyl, and heterocyclyl are optionally substituted with halogen, CN and -OMe;
  • each R 4 and R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, nitro, amino, mercapto, -COOH, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkylester, C 1 -C 6 thioalkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, (mono- and di-C 1 -C 6 alkylamino) C 0 -C 4 alkyl, -
  • the compound has the structure of formula (Ia) :
  • X 1 and X 2 are each independently selected from the group consisting of a bond, - (CH 2 ) n -, -CH (R 1 ) (CH 2 ) n -, -C (O) -, and -S (O) 2 -;
  • Ring B is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 3 ;
  • Ring D is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl, wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 5 ;
  • Ring E is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl, wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 6 ;
  • n 0, 1, 2 or 3
  • each R 1 is independently selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, and halogen;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • each R 3 and R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkylester, C 1 -C 6 thioalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and 3 to 8-membered heterocyclyl, wherein the cycloalkyl, and heterocyclyl are optionally substituted with halogen, CN and -OMe;
  • each R 4 and R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, and -OH.
  • X 1 is -CH 2 -or -CD 2 -.
  • the compound has the structure of formula (I-1) :
  • R m is independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, and -OH;
  • X’ 1 is - (CH 2 ) m -, -CH (R n1’ ) (CH 2 ) m -, -C (O) -, or -S (O) 2 -;
  • R n1, R n2 and R n1’ are each independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 6 identical or different substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl;
  • n 0, 1, 2, or 3.
  • X’ 1 is - (CH 2 ) - or - (CD 2 ) -.
  • Ring B’ is selected from the group consisting of 4 to 6 membered monocyclic heterocyclyl, preferably Ring B’ is selected from the group consisting of piperazinyl and piperidinyl.
  • R n1, R n2 and R n1’ are each independently selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • the compound has the structure of formula (I””)
  • Ring A’ is independently selected from the group consisting of C 6 -C 10 aryl, monocyclic 5-or 6-membered heteroaryl, bicyclic 9-or 10-membered heteroaryl, and tricyclic 12-, 13-or 14-membered heteroaryl, wherein the heteroaryl has 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N, wherein the aryl, and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 2’ ;
  • each R 2’ is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • R n3 is independently selected from the group consisting of C 3 -C 8 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 6 identical or different substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, and -OH;
  • R n4 is independently selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl; wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with 1 to 6 identical or different substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 4 to 10 membered monocyclic or bicyclic heterocyclyl;
  • g 1 and g 2 are each independently 0, 1 or 2.
  • Ring A’ has the same definition as Ring A.
  • Ring A is 9-membered heteroaryl, and preferably, Ring A is
  • R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • Y 1 , Y 2 , Y 3 , Y 4 and Y 5 are each independently selected from the group consisting of C, CH, N, O, S and CO;
  • W 1 , W 2 , W 3 and W 4 are each independently selected from the group consisting of C, and N.
  • Ring A is wherein is a single bond or a double bond
  • R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
  • Y 1 and Y 2 are each independently selected from the group consisting of C, CH, N, O, S and CO;
  • W 3 is independently selected from the group consisting of C, and N.
  • Ring A is selected from the group consisting of
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl and C 1 -C 6 haloalkyl.
  • Ring B is selected from the group consisting of
  • Y 6 is independently selected from the group consisting of CH and N;
  • Z 1 and Z 2 are each independently selected from the group consisting of CH and N;
  • each R 3 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkylester, C 1 -C 6 thioalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and 3 to 8-membered heterocyclyl, wherein the cycloalkyl, and heterocyclyl are optionally substituted with halogen, CN and -OMe;
  • p 0, 1, 2, 3 or 4.
  • Ring B is selected from the group consisting of,
  • Ring B is selected from the group consisting of
  • the compound has a structure represented by a formula selected from the following formulas,
  • each X 2 is independently selected from the group consisting of a bond, - (CH 2 ) n -, -CH (R 1 ) (CH 2 ) n -, -C (O) -, and -S (O) 2 -;
  • Y 6 is independently selected from the group consisting of CH and N;
  • p 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3;
  • R 1 , R 2 , R 3 , Ring D and Ring E are defined as above.
  • the compound has a structure of formula (III)
  • R 2 , R 3 , X 2 , p, Y 6 , Ring D and Ring E are defined as above.
  • the compound has a structure of formula (IV)
  • R 2 , R 3 , X 2 , Y 6 , Ring D and Ring E are defined as above.
  • the compound has a structure represented by a formula selected from the following formulas
  • R 2 , R 3 , X 2 , Y 6 , Ring D and Ring E are defined as above.
  • the compound has a structure represented by a formula selected from the following formulas:
  • R 2 , R 3 , X 2 , Y 6 , Ring D and Ring E are defined as above.
  • Ring D is selected from the group consisting of C 3 -C 7 cycloalkyl (preferably, C 3 -C 6 cycloalkyl) , 4-8-membered heterocyclyl (preferably, 4-7-membered heterocyclyl) , wherein the cycloalkyl and heterocyclyl are optionally substituted with 1 to 6 identical or different substituents R 5 ;
  • Ring D is selected from the group consisting of
  • each R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyl, C 2 -C 6 alkylester, C 1 -C 6 thioalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, hydroxy C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, and 3 to 8-membered heterocyclyl, wherein the cycloalkyl, and heterocyclyl are optionally substituted with halogen, CN and -OMe; or two R 5 on non-adjacent carbon atoms together with the non-ad
  • Y 7 is independently selected from the group consisting of CH and N;
  • q 0, 1, 2 or 3;
  • Ring D is selected from the group consisting of
  • each R 5 is independently selected from the group consisting of hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 haloalkyl.
  • the compound has a structure represented by a formula selected from the following formulas:
  • R 2 , R 3 , R 5 , X 2 , q, Y 6 , Y 7 , and Ring E are defined as above.
  • the compound has a structure represented by a formula selected from the following formulas:
  • R 2 , R 3 , R 5 , X 2 , q, Y 6 , and Ring E are defined as above.
  • the compound has a structure represented by a formula selected from the following formulas:
  • R 2 , R 3 , R 5 , X 2 , q, Y 6 , and Ring E are defined as above.
  • Ring E is selected from the group consisting of C 3 -C 6 cycloalkyl, 4 to 6-membered heterocyclyl, C 6 -C 10 aryl, and 5 to 10-membered heteroaryl; wherein the heterocyclyl, and heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with 1 to 6 identical or different substituents R 6 ;
  • each R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkynyloxy, -CN, -OH, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, C 5 -C 10 heteroaryl.
  • Ring E is wherein respectively represents that a hydrogen of any one of CH in is independently substituted with a R 6 .
  • Ring E is wherein, W 5 , W 6 , W 7 , W 8 , W 9 , for each occurrence, is independently selected from CH, CD, N, O, S, N (R 6 ) , and CR 6 .
  • Ring E is a 5-to 9-membered heteroaryl, wherein the heteroaryl have 1, 2 or 3 heteroatoms as ring members which are each independently selected from the group consisting of O, S, and N; wherein the heteroaryl are optionally substituted with 1 to 3 identical or different substituents R 6 ;
  • each R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl.
  • Ring E is a 5-membered heteroaryl having 2 nitrogen atoms; wherein the heteroaryl are optionally substituted with 1 to 3 identical or different substituents R 6 ;
  • each R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl.
  • Ring E is wherein respectively represents that e hydrogens of CH or CH 2 in are independently substituted with e identical or different substituents of R 6 ; e is 0, 1, 2, 3, 4, or 5.
  • Ring E is selected from the group consisting of C 3 -C 6 cycloalkyl, 4-6 membered heterocyclyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl, pyrazolyl, indazolyl; wherein the cycloalkyl, heterocyclyl, thiazolyl, imidazolyl, oxazolyl, isoxazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, indazolyl are optionally substituted with 1 to 6 identical or different substituents R 6 ;
  • each R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkynyloxy, -CN, -OH, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl, C 5 -C 10 heteroaryl.
  • Ring E is selected from the group consisting of
  • each R 6 is independently selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -CN, -OH, C 3 -C 8 cycloalkyl, 3 to 8-membered heterocyclyl.
  • e 0, 1, 2, 3, 4, or 5;
  • Ring E is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
  • R 6 for each occurrence, is independently selected from the group consisting of F, Cl, Br, methyl, ethyl, isopropyl, cyclopropyl, -CF 3 , -CHF 2 .
  • R 2 is F, Cl, Br, Me, -CF 3 , -CHF 2 .
  • R 2 is F, Cl, Br.
  • X 2 is a bond or -CH 2 -.
  • R 3 is methyl, ethyl, cyclopropyl.
  • each R 5 is hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl; preferably, each R 5 is hydrogen, F, Cl, Br, methyl, ethyl.
  • q 0, 1, 2 or 3;
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • composition comprising a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition is a tablet, a capsule, a granule, a syrup, a suspension, a solution, a dispersion, a slowed release preparation for oral or non-oral administration, an intravenous injection preparation, a subcutaneous injection preparation, an inhalation preparation, a transdermal preparation, a rectal or vaginal suppository.
  • the third aspect it provides a use of a compound of any one of the first aspect of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof in the manufacture of a medicament for the treatment of a disease or disorder that is affected by the degradation of WIZ protein.
  • it provides a compound of the first aspect of the present invention, or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof, for use in the treatment of a disease or disorder affected by reactivating or increasing fetal hemoglobin expression in a subject in need thereof.
  • the fourth aspect provides a method of inhibiting, reducing, or eliminating the activity of WIZ protein or WIZ protein expression in a subject in need thereof, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of the first aspect of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • a disease or disorder includes sickle cell anemia, and beta-thalassemia.
  • alkyl refers to a branched or straight chain saturated aliphatic hydrocarbon group. In one embodiment, the alkyl contains from 1 to about 12 (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12) carbon atoms, more generally from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one embodiment, the alkyl contains from 1 to about 8 carbon atoms. In certain embodiments, the alkyl is C 1 -C 2 , C 1 -C 3 , or C 1 -C 6 .
  • the specified ranges as used herein indicate an alkyl group having each member of the range described as an independent species.
  • C 1 -C 6 alkyl indicates a straight or branched alkyl group having from 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2, 2-dimethylbutyl and 2, 3-dimethylbutyl.
  • the alkyl group is optionally substituted as described herein.
  • alkenyl refers to a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds that may occur at a stable point along the chain.
  • Nonlimiting examples are C 2 -C 6 alkenyl (such as C 2 , C 3 , C 4 , C 5 , C 6 ) and C 2 -C 4 alkenyl.
  • the specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described herein for the alkyl moiety.
  • alkenyl examples include, but are not limited to, ethenyl, propenyl, butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl) .
  • the alkenyl group is optionally substituted as described herein.
  • alkynyl refers to a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C 2 -C 6 alkynyl (such as C 2 , C 3 , C 4 , C 5 , C 6 ) .
  • the specified ranges as used herein indicate an alkynyl group having each member of the range described as an independent species, as described herein for the alkyl moiety.
  • alkynyl examples include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • the alkynyl group is optionally substituted as described herein.
  • alkoxy refers to an alkyl group as defined above with the indicated number of carbon atoms covalently bound through an oxygen bridge (-O-) .
  • alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
  • an “alkylthio” or a “thioalkyl” group is an alkyl group as defined above with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-) .
  • Examples of thioalkyl include, but are not limited to, CH 3 -S-, CH 3 CH 2 -S-and CH 3 -S-CH 2 -.
  • the alkoxy group is optionally substituted as described herein.
  • alkenyloxy refers to an alkenyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-O-) .
  • alkynyloxy refers to an alkynyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-O-) .
  • alkylester refers to an alkyl group as defined with the indicated number of carbon atoms covalently bound through an ester linkage.
  • cycloalkyl refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems.
  • cycloalkyl includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond) .
  • C 3 -C 8 cycloalkyl is constructed by 3 to 8 ring carbon atoms (such as, 3, 4, 5, 6, 7 or 8 ring carbon atoms) .
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and partially unsaturated groups such as cyclopentenyl and cyclohexenyl.
  • amide or “carboxamide” refers to -C (O) NR c R d , wherein R c and R d are each independently selected from hydrogen, alkyl, for example, C 1 -C 6 alkyl, alkenyl, for example, C 2 -C 6 alkenyl, alkynyl, for example, C 2 -C 6 alkynyl, -C 0 -C 4 alkyl (C 3 -C 7 cycloalkyl) , -C 0 -C 4 alkyl (C 3 -C 7 heterocycloalkyl) , -C 0 -C 4 alkyl (aryl) , and -C0-C4alkyl (heteroaryl) ; or together with the nitrogen to which they are bonded, R c and R d can form a C 3 -C 7 heterocyclic ring.
  • the R c and R d groups are each independently optionally substituted as
  • haloalkyl refers to both branched and straight-chain alkyl groups substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, monofluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • haloalkoxy refers to a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical) .
  • halo or halogen refers to independently any of fluoro, chloro, bromo, and iodo.
  • aryl refers to aromatic groups containing only carbon in the aromatic ring or rings.
  • the aryl groups contain 1 to 3 separate or fused rings and 6 to about 10 ring atoms (i.e. C 6 -C 10 , such as 6, 7, 8, 9, 10 ring atoms) , without heteroatoms as ring members.
  • aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3, 4-methylenedioxyphenyl group.
  • Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, fluorenyl, and anthryl.
  • aryl groups are pendant.
  • An example of a pendant ring is a phenyl group substituted with a phenyl group.
  • the aryl group is optionally substituted as described herein.
  • heterocyclyl refers to a saturated or a partially unsaturated (i.e., having one or more double and/or triple bonds within the ring without aromaticity) monocyclic or bicyclic radical of 4, 5, 6, 7, 8, 9, or 10 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen, and sulfur, the remaining ring atoms being C, where one or more ring atoms is optionally substituted independently with one or more substituents described above.
  • the only heteroatom is oxygen.
  • a heterocyclyl may be a monocycle having 4 to 7 ring members (2 to 6 carbon atoms and 1 to 4 heteroatoms selected from N, O, and S) or a bicycle having 6 to 10 ring members (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, and S) , for example: a bicyclo [4, 5] , [5, 5] , [5, 6] , or [6, 6] system.
  • the only heteroatom is sulfur.
  • heterocyclic rings include, but are not limited to, pyrrolidinyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, piperidonyl, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydro
  • heteroaryl can be a stable monocyclic aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5-to 7-membered aromatic ring which contains from 1 to 3, or in some embodiments from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon.
  • the 5 to 10 membered heteroaryl described herein may contain 5, 6, 7, 8, 9 or 10 ring atoms.
  • the only heteroatom is nitrogen.
  • the only heteroatom is oxygen.
  • the only heteroatom is sulfur.
  • Monocyclic heteroaryl groups typically have from 5 to 7 ring atoms.
  • bicyclic heteroaryl groups are 9-to 10-membered heteroaryl groups, that is, groups containing 9 or 10 ring atoms in which one 5-to 7-member aromatic ring is fused to a second aromatic or nonaromatic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, pyridinyl (including, for example, 2-pyridinyl, 2-hydroxypyridinyl, 3-pyridinyl, 3-hydroxypyridinyl, 4-pyridinyl, 4-hydroxypyridinyl) , imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl) , pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a moiety selected from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • Ring system When a Ring system is substituted with a substituent, it means that the substituent is attached to an aromatic or nonaromatic ring system and replaces an available hydrogen on the ring system. Particularly, represents that a hydrogen of any one of CH in the ring system of is substituted with a R 2 , that is, has a formula selected from the group consisting of wherein R 2 is as defined above.
  • the compound of the present invention refers to the compound represented by the formula I, and further comprises the pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.
  • the salt of the compound in the present invention may be formed which is also within the scope of the present invention. Unless otherwise stated, the compound in the present invention is understood to include its salt.
  • the term "salt” as used herein refers to a salt formed in the form of acid or base from inorganic or organic acid and base. Further, when the compound in the present invention contains a base fragment which includes, but is not limited to pyridine or imidazole, when contains an acid segment which includes, but is not limited to carboxylic acid.
  • the zwitter-ion that may form “inner salt” is included within the range of the term “salt” .
  • compositions of the present invention may form a salt, for example, compound I is reacted with a certain amount (such as an equivalent amount) of an acid or base, and precipitated in a medium, or freeze-dried in aqueous solution.
  • the compounds in the present invention containing base fragments which include but arenot limited to amines or pyridine or imidazole rings, may form salt with organic or inorganic acid.
  • Typical acids that form salts include acetate (e.g., acetate or trihalogenated acetic acid, e.g., trifluoroacetic acid) , adipate, alginate, ascorbate, aspartate, benzoate, benzene sulfonate, disulfate, borate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane propionate, diethylene glycolate, lauryl sulfate, ethanesulphonate, fumarate, gluceptate, glycerophosphate, hemisulphate, enanthate, caproate, hydrochloride, hydrobromide, hydriodate, isethionate (e.g., 2-hydroxy-ethesulfon
  • Some compounds of the invention may contain acidic fragments including, but not limited to carboxylic acid may form salts with various organic or inorganic bases.
  • Salts formed by typical bases includes ammonium salt, alkali metal salt (such as sodium, lithium and potassium salts) , alkaline earth metal salt (such as calcium and magnesium salts) , and salts formed by organic bases (e.g., organic amines) , such as benzathine, dicyclohexylamine, hydrabamine (salt formed with N, N-bis (dehydroabietyl) ethylenediamine) , N-methyl-D-glucanamine, N-methyl-D-glucoamide, tert-butyllamine, and the salts formed with amino acids such as arginine, lysine, etc.
  • alkali metal salt such as sodium, lithium and potassium salts
  • alkaline earth metal salt such as calcium and magnesium salts
  • organic bases e.g., organic amines
  • organic bases e
  • Basic nitrogen-containing groups can form quaternary ammonium salts with halides, such as small molecular alkyl halides (e.g., chlorides, bromides and iodides of methyl, ethyl, propyl and butyl) , dialkyl sulfates (such as dimethyl, diethyl, dibutyl, and dipentyl sulfates) , long chain halides (e.g., chlorides, bromides and iodides of decyl, dodecyl, tetradecyl, and tetradecyl) , aralkyl halides (such as bromides of benzyl and phenyl) , etc.
  • halides such as small molecular alkyl halides (e.g., chlorides, bromides and iodides of methyl, ethyl, propyl and butyl) , dialkyl sulfates
  • prodrug and solvate of the compound in the present invention are also included within the scope of the present invention.
  • prodrug herein refers to a compound resulting from the chemical transformation of a metabolic or chemical process to produce a compound, salt, or solvate in the present invention for the treatment of an associated disease.
  • the compounds of the invention include solvates such as hydrates.
  • Compound, salt or solvate in the present invention may be present in tautomeric forms such as amide and imino ether. All of these tautomers are part of the present invention.
  • Stereoisomers of all compounds e.g., those asymmetric carbon atoms that may be present due to various substitutions
  • the independent stereoisomer in the present invention may not coexist with other isomers (e.g., as a pure or substantially pure optical isomer with special activity) , or may be a mixture (e.g., racemate) , or a mixture formed with all other stereoisomers or a part thereof.
  • the chiral center of the present invention has two configurations of S or R, which is defined by International Union of Pure and Applied Chemistry (IUPAC) founded in 1974.
  • racemization form can be solved by physical methods, such as fractional crystallization, or separation crystallization by derivation into diastereomers, or separation by chiral column chromatography.
  • Individual optical isomer can be obtained from racemate by appropriate methods, including but not limited to conventional methods, such as recrystallization after salting with optically active acids.
  • stereocenter When a stereocenter is designated as “*R” or “*S” , it means that the absolute stereochemistry for such a stereocenter is undetermined (even if the bonds are drawn stereo specifically) although it is in a substantially single steric configuration.
  • “*R” can be absolute R configuration, or absolute S configuration.
  • “*S” can be absolute R configuration, or absolute S configuration.
  • “*R” or “*S” is assigned randomly for such molecules.
  • a stereocenter designated as “*R” can be in a single steric configuration same as or different from that of another stereocenter designated as “*S” .
  • a stereocenter designated as “*R” can be in a single steric configuration same as or different from that of another stereocenter designated as “*R” .
  • a stereocenter designated as “*S” can be in a single steric configuration same as or different from that of another stereocenter designated as “*S” .
  • Weight content of compound in the present invention obtained by preparation, separation and purification in turn is equal to or greater than 90%, such as equal to or greater than 95%, equal to or greater than 99% ( “very pure” compound) , and listed in the description of the text.
  • “very pure” compound of the present invention is also part of the present invention.
  • All configuration isomers of the compound of the present invention are within the scope, whether in mixture, pure or very pure form.
  • the definition of the compound of the present invention comprises cis (Z) and trans (E) olefin isomers, and cis and trans isomers of carbocyclic and heterocyclic.
  • Some compounds of the present invention may exist in specific geometric or stereoisomer forms.
  • the present invention covers all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) type isomers, (L) type isomers, racemic mixtures and other mixtures.
  • asymmetric carbon atom can represent substituent, such as alkyl. All isomers and mixtures thereof are included in the present invention.
  • mixtures of isomers may contain a variety ratio of isomers.
  • mixtures with only two isomers may have the following combinations: 50: 50, 60: 40, 70: 30, 80: 20, 90: 10, 95: 5, 96: 4, 97: 3, 98: 2, 99: 1, or 100: 0, all ratios of the isomers are within the scope of the present invention.
  • Similar ratio and the ratio of mixtures of more complex isomers, which are readily understood by general skill of the art are also within the scope of the invention.
  • the present invention also includes the isotope labeled compound, which is equivalent to the original compound herein. However, in fact, the substitution of one or more atoms by an atom with a different atomic weight or mass number usually occurs.
  • Examples of compound isotopes that may be listed in the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • isotope-labeled compounds in the present invention such as the radioactive isotopes of 3 H and 14 C, are also included and are useful in experiments on the tissue distribution of drugs and substrates. Tritium ( 3 H) and Carbon-14 ( 14 C) , which are relatively easy to prepare and detect. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, have advantages in certain therapies due to their good metabolic stability, such as increased half-life or reduced dosage in vivo, and thus may be preferred in certain situations. Isotope-labeled compounds can be prepared by conventional methods through replacing readily available isotope-labeled reagents with non-isotopic reagents that can be prepared using the disclosed scheme shown in the Example.
  • the synthesis of the compound of the invention can be prepared by asymmetric synthesis, or derivatized with chiral auxiliary reagent, separating the resulting diastereomeric mixture and removing the chiral adjunct to obtain a pure enantiomer.
  • a molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group
  • a diastereomer can be formed with a salt of suitable optically active acids or bases, which can be separated by conventional means, such as crystallization or chromatography, to obtain a pure enantiomer.
  • the compound in the present invention may be substituted with any number of substituents or functional groups to extend its scope.
  • the general formula that includes substituents in the compound of the present invention means the substitution of a specified structural substituent for a hydrogen radical. When multiple locations in a particular structure are replaced by multiple specific substituents, each location of the substituents can be the same or different.
  • substituted as used herein includes all substitution that allows organic compounds to be substituted.
  • the allowable substituents include non-annular, cyclic, branched, non-branched, carbocyclic and heterocyclic, aromatic ring and non-aromatic organic compounds.
  • such as heteroatomic nitrogen its valence state may be supplemented by a hydrogen substituent or by any permitted organic compound described above.
  • the invention is unintentionally limited to the substituted organic compounds.
  • the present invention considers that a combination of substituents and variable groups is good for the treatment of diseases (such as infectious or hypertrophic diseases) in the form of stable compounds.
  • stable herein refers to a stable compound which is sufficient for maintaining the integrity of the compound structure within a sufficiently long time, preferably in a sufficiently long time, which is hereby used for the above purposes.
  • the preparation method of the compound of the formula (I) of the present invention is more specifically described below, but these specific methods do not constitute any limitation of the invention.
  • the compound of the invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such a combination may be easily performed by a skilled person in the art to which the invention belongs.
  • compositions of the present invention are used to prevent and /or treat a disease or disorder that is affected by the degradation of WIZ protein, such as sickle cell disease, beta-thalassemia, anemia, or related hemoglobinopathy.
  • the compounds of the formula (I) may be used in combination with other drugs known to treat or improve similar conditions.
  • the original administration for the drug can remain unchanged, while compound of formula I may be administered simultaneously or subsequently.
  • Pharmaceutical composition containing one or more known drugs and the compound of formula I may be preferred when administered in combination with one or more other drugs.
  • the drug combination also includes administering the compound of formula I and other one or more known drugs at overlapping time. When the compound of formula I is combined with other one or more drugs, the dose of the compound or known drug may be lower than that of their individual use.
  • the dosage forms of the pharmaceutical composition of the present invention include (but are not limited to) : injection, tablet, capsule, aerosol, suppository, pellicle, pill, liniment for external use, controlled release or sustained-release or nano formulation.
  • the pharmaceutical composition of the present invention comprises a compound of the present invention or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient or carrier with safe and effective amount.
  • safe and effective amount refers to the amount of compound is sufficient to significantly improve the condition, not to produce severe side effects.
  • the pharmaceutical composition contains 1-2000 mg of the compound /dosage of the present invention, and preferably contains 1-1000 mg of the compound /dosage of the present invention.
  • "one dosage" is a capsule or a pill.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid filler or gel substances, which are suitable for human use, and must be sufficiently pure and of sufficiently low toxicity. "Compatible” herein refers to the ability of each component of a composition can be mixed with the compound of the present invention and can be mixed with each other without appreciably reducing the efficacy of the compound.
  • pharmaceutically acceptable carrier include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as talc, solid lubricant (such as stearic acid, magnesium stearate) , calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc. ) , polyol (such as propylene glycol, glycerol, mannitol, sorbitol, etc. ) , emulsifier (such as ) , wetting agent (such as lauryl sodium sulfate) , colorant, flavoring, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • solid lubricant such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil, peanut oil, olive oil, etc.
  • polyol such as propylene glycol, glycerol, mannitol, sorbitol, etc.
  • emulsifier such as )
  • wetting agent such as lauryl sodium
  • administration mode for the compound or pharmaceutical compositions of the present invention
  • representative administration mode includes (but is not limited to) : oral, intratumorally, rectal, parenteral (intravenous, intramuscular or subcutaneous) , and topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compounds are mixed with at least one conventional inert excipient (or carrier) , such as sodium citrate or dicalcium phosphate, or mixed with any of the following components: (a) fillers or compatibilizer, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (c) humectant, such as, glycerol; (d) disintegrating agent, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain composite silicates, and sodium carbonate; (e) dissolution-retarding agents, such as paraffin; (f) absorption accelerators, such as quaternary ammonium compounds; (g) wetting agents, such as
  • the solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared by using coating and shell materials, such as enteric coatings and any other materials known in the art. They can contain an opaque agent.
  • the release of the active compounds or compounds in the compositions can be released in a delayed mode in a given portion of the digestive tract.
  • the embedding components include polymers and waxes. If necessary, the active compounds and one or more above excipients can form microcapsules.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • the liquid dosage forms may contain any conventional inert diluents known in the art such as water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1, 3-butanediol, dimethyl formamide, as well as oil, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or the combination thereof.
  • composition may also contain additives such as wetting agents, emulsifiers, suspending agent, sweetener, flavoring agents and perfume.
  • additives such as wetting agents, emulsifiers, suspending agent, sweetener, flavoring agents and perfume.
  • the suspension may contain suspending agent, for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol aluminum and agar, or the combination thereof.
  • suspending agent for example, ethoxylated isooctadecanol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, methanol aluminum and agar, or the combination thereof.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders which can be re-dissolved into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and any suitable mixtures thereof.
  • the dosage forms for topical administration of compounds of the invention include ointments, powders, patches, aerosol, and inhalants.
  • the active ingredients are mixed with physiologically acceptable carriers and any preservatives, buffers, or propellant if necessary, under sterile conditions.
  • Compounds of the present invention can be administrated alone, or in combination with any other pharmaceutically acceptable compounds.
  • a safe and effective amount of compound of the present invention is administered to a mammal (such as human) in need thereof, wherein the dose of administration is a pharmaceutically effective dose.
  • the daily dose is usually 1-2000 mg, preferably 50-1000mg.
  • the particular dose should also depend on various factors, such as the route of administration, patient health status, which are well within the skills of an experienced physician.
  • the present invention also provides a preparation method of pharmaceutical composition comprising the step of mixing a pharmaceutically acceptable carrier with the compound of formula (I) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomer thereof of the present invention.
  • the main advantages of the present invention include:
  • the compounds described in the present invention are effective to reduce or modulate widely interspaced zinc finger motifs (WIZ) protein expression levels and/or induce fetal hemoglobin (HbF) expression.
  • WIZ widely interspaced zinc finger motifs
  • HbF fetal hemoglobin
  • the compounds described in the present invention possess a low clearance rate, good oral exposure, and high oral bioavailability.
  • the starting materials of A-1 is halogenated under the condition of NBS, or NIS or Br 2 under the solvent of ACN, DMF or DCM, then the intermediate is oxidated under the condition of MnO 2 or other oxidizing reagents.
  • a piperazine derivative is coupling with the aldehyde in presence of NaBH (AcO) 3 with the catalysis of AcOH to yield the compound A-2.
  • the compound A-2 is subjected to Buchwald-Hartwig reaction to produce the compound A-3 in presence of Pd catalysis or Ullmann reaction in presence of Cu catalysis in a solvent (such as dioxane, DMF, or DMSO) .
  • a solvent such as dioxane, DMF, or DMSO.
  • the protective groups of compound A-3 can be removed by HCl/dioxane, TFA, or TFA and TfOH to yield the deprotected compound A-4.
  • the compound of formula II (1-2) can be synthesized through a reductive amination of compound A-4 with an appropriate aldehyde or ketone in the presence of a reducing agent (for example NaBH 3 CN) and AcOH.
  • a reducing agent for example NaBH 3 CN
  • compound of formula II (1-2) can be synthesized through an alkylation reaction of compound A-4 using an appropriate alkyl halide, mesylate, tosylate or triflate in the presence of an amine or carbonate base and polar solvent, such as DIPEA or K 2 CO 3 and DMF.
  • polar solvent such as DIPEA or K 2 CO 3 and DMF
  • compounds of the formula II (1-2) of the invention may be made using conventional organic syntheses and commercially available starting materials.
  • Compound B-2 is produced through Suzuki reaction and halogenation. Under appropriate temperature and N 2 protection, the compound B-1 reacts with a boronic derivative in presence of Pd catalysis, ligand, and base (for example, t-BuOK, Cs 2 CO 3, NaH) in an organic solvent (for example, THF, Toluene, DMF, dioxane, et al. ) . The yield depends on the substrates, Pd and ligand. To provide compound B-2, halogenation is carried out under the conditions of NBS, or NIS or Br 2 .
  • the second step is followed by General step 2.
  • the compound B-2 is treated to Buchwald-Hartwig reaction in presence of Pd catalysis or Ullmann reaction in presence of Cu catalysis in a solvent (such as dioxane, DMF, or DMSO) .
  • a solvent such as dioxane, DMF, or DMSO
  • Boc group of compound B-3 is removed by HCl/dioxane or other conditions, such as TFA.
  • the compound of formula II (1-2) can be synthesized through reductive amination or alkylation as described in scheme 1, followed by the removal of the protective group Pusing TFA/TFOH, wherein W 3 , Y 2 , Y 1, ring D and ring E are as defined in the claim.
  • compounds of formula II-3 of the invention may be prepared using conventional organic syntheses and commercially available starting materials.
  • the bromo C-2 can be substituted through Suzuki reaction.
  • the bromo can be reacted with a boraneyl derivative in presence of Pd-catalysis (such as Ruphos Pd G3) , a solvent, such as DMF or dioxane, a base, such as Cs 2 CO 3 .
  • Pd-catalysis such as Ruphos Pd G3
  • a solvent such as DMF or dioxane
  • a base such as Cs 2 CO 3 .
  • the primary amide and amino groups of C-3 are cyclized with a carbonyl equivalent to form a dihydrouracil moiety, such as 1, 1’-carbonyldiimidazole (CDI) in the presence of an amine or carbonate base, such as Cs 2 CO 3 , and a polar solvent, such as acetonitrile.
  • a protective group e.g., Boc
  • C-4 can then be converted to formula II-3 by reductive amination with an appropriate aldehyde in the presence of a borohydride reagent, such as NaBH 3 CN; alternatively, by an alkylation reaction with an appropriate alkyl halide, mesylate, tosylate or triflate in the presence of an amine or carbonate base and polar solvent, such as DIPEA or K 2 CO 3 and DMF.
  • a borohydride reagent such as NaBH 3 CN
  • an alkylation reaction with an appropriate alkyl halide, mesylate, tosylate or triflate in the presence of an amine or carbonate base and polar solvent, such as DIPEA or K 2 CO 3 and DMF.
  • ACN means acetonitrile
  • AcOH means acetic acid
  • Boc means tert-butyloxycarbonyl
  • Bn means benzyl
  • BH 3 means borane
  • t-BuOK means potassium tert-butoxide
  • BINAP means 1.1'-binaphthyl-2.2'-diphemyl phosphine
  • calcd. means calculated
  • Cbz means benzyloxycarbonyl
  • col. means column, conc.
  • CDI means 1, 1'-carbonyldiimidazole
  • DCM means dichloromethane
  • DIEA or DIPEA means N, N-diisopropylethyl amine
  • DMF means dimethylformamide
  • DMP means Dess-Martin periodinane
  • DMSO means dimethyl sulphoxide
  • DPPP means 1, 3-bis (diphenylphosphine) propane
  • Et 3 N means triethylamine
  • EtOAc or EA means ethyl acetate
  • ee means enantiomeric excess
  • ESI means electrospray ionization
  • FA means formic acid
  • HATU means 2- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate
  • Hex means hexane
  • HNMR means 1 H NMR
  • HCI means hydrochloric acid
  • HPLC means high performance
  • Prep-HPLC means preparative
  • PCC means pyridinium chlorochromate
  • PdCl 2 (dppf) means [1, T-Bis (diphenylphosphino) ferrocene] dichloropalladium (II)
  • Pd 2 (dba) 3 means tris (dibenzylideneacetone) dipalladium (0)
  • t R or Rt mean retention time
  • (s) or (s) mean solid, sat.
  • TMS means trimethylsilyl
  • TsCl means 4-toluenesulfonyl chloride
  • Tf 2 O means trifluoromethanesulfonic anhydride
  • TfOH means trifluoromethanesulfonic
  • K 2 CO 3 means potassium carbonate
  • RuPhos Pd G3 means RuPhos-G3-Palladacycle
  • Step 1 Synthesis of ( ( (3S) -4- (tert-butoxycarbonyl) -3-methylpiperazin-1-ium-1-yl) methyl) trifluoroborate
  • Step 2 Synthesis of potassium (S) - ( (4- (tert-butoxycarbonyl) -3-methylpiperazin-1-yl) methyl) trifluoroborate
  • Step 1 Synthesis of tert-butyl (S) -2-methyl-4- (pyrazolo [1, 5-a] pyridin-5-ylmethyl) piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl (S) -4- ( (3-iodopyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl (S) -4- ( (3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazi ne-1-carboxylate
  • Step 4 Synthesis of (S) -3- (4-methoxybenzyl) -1- (5- ( (3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione hydrochloride
  • Step 5 Synthesis of (S) -1- (5- ( (3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 Synthesis of tert-butyl (2S) -2-methyl-4- (pyrazolo [1, 5-a] pyridine -5-carbonyl) piperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl (2S) -2-methyl-4- (pyrazolo [1, 5-a] pyridin-5-ylmethyl) piperazine-1-carboxylate
  • Step 1 Synthesis of (1-aminopyridin-1-ium-4-yl) methanol; 2, 4-dinitrophenolate
  • Step 3 Synthesis of (2-fluoropyrazolo [1, 5-a] pyridin-5-yl) methanol
  • Step 4 Synthesis of 2-fluoropyrazolo [1, 5-a] pyridine-5-carbaldehyde
  • Step 5 Synthesis of tert-butyl (S) -4- ( (2-fluoropyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 6 Synthesis of tert-butyl (S) -4- ( (3-bromo-2-fluoropyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 7 Synthesis of tert-butyl (S) -4- ( (2-fluoro-3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 8 Synthesis of (S) -1- (2-fluoro-5- ( (3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 Synthesis of 4- (4- (dimethoxymethyl) piperidin-1-yl) -3-fluorobenzonitrile
  • Step 3 Synthesis of (S) -3-fluoro-4- (4- ( (4- ( (3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpipe razin-1-yl) methyl) piperidin-1-yl) benzonitrile
  • the mixture was stirred at 50 °C for 16 hrs.
  • the reaction mixture was cooled to 20 °C, and NaBH 3 CN (21.7 mg, 344 ⁇ mol) was added.
  • the mixture was stirred at 20 °C for 2 hrs.
  • the mixture was concentrated under reduced pressure.
  • Step 4 Synthesis of compound 1: (S) -4- (4- ( (4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidin-1-yl) -3-fluorobenzonitrile
  • Step 1 Synthesis of ethyl 4- (4-fluorophenyl) cyclohex-3-ene-1-carboxylate
  • Step 2 Synthesis of ethyl 4- (4-fluorophenyl) cyclohexane-1-carboxylate
  • Step 3 Synthesis of 4- (4-fluorophenyl) cyclohexane-1-carboxylic acid
  • Step 5 Synthesis of 4- (4-fluorophenyl) cyclohexanecarbaldehyde
  • Step 6 Synthesis of (S) -1- (5- ( (4- ( (4- (4-fluorophenyl) cyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • the mixture was stirred at 50 °C for 2 hrs.
  • the reaction mixture was cooled to 20 °C, and NaBH 3 CN (17.6 mg, 280.6 ⁇ mol) was added.
  • the mixture was stirred at 20 °C for 14 hrs.
  • the mixture was concentrated under reduced pressure.
  • Step 7 Synthesis of compound 2: (S) -1- (5- ( (4- ( (4- (4-fluorophenyl) cyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 Synthesis of 4- (dimethoxymethyl) -1- (4-fluorophenyl) piperidine
  • Step 3 Synthesis of (S) -1- (5- ( (4- ( (1- (4-fluorophenyl) piperidin-4-yl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 4 Synthesis of compound 3: (S) -1- (5- ( (4- ( (1- (4-fluorophenyl) piperidin-4-yl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 4 preparation of compound 4: (S) -6- (4- ( (4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidin-1-yl) nicotinonitrile
  • Step 1 Synthesis of tert-butyl (S) -4- ( (4- ( (3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidine-1-carboxylate
  • Step 2 Synthesis of (S) -3- (4-methoxybenzyl) -1- (5- ( (3-methyl-4- (piperidin-4-ylmethyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 3 Synthesis of (S) -6- (4- ( (4- ( (3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidin-1-yl) nicotinonitrile
  • Step 4 Synthesis of compound 4: (S) -6- (4- ( (4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidin-1-yl) nicotinonitrile
  • Step 1 Synthesis of methyl 1- (3-fluoro-4-methoxyphenyl) azetidine-3-carboxylate
  • Step 2 Synthesis of 1- (3-fluoro-4-methoxyphenyl) azetidine-3-carbaldehyde
  • Diisobutylalumane (1.5 M, 1.25 mL, 1.88 mmol) was added in a dropwise manner to a solution of methyl 1- (3-fluoro-4-methoxy-phenyl) azetidine-3-carboxylate (300 mg, 1.25 mmol) in DCM (15 mL) at -78 °C. The mixture was stirred at -78 °C for 0.5 hr. The mixture was quenched with 50%aqueous rochelle salt aqueous solution (10 mL) at 0 °C. The mixture was stirred at 25 °C for 3 hrs. The mixture was poured into water (10 mL) and extracted with DCM (20 mL x 2) .
  • Step 3 Synthesis of compound 5: (S) -1- (5- ( (4- ( (1- (3-fluoro-4-methoxyphenyl) azetidin-3-yl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • the mixture was stirred at 50 °C for 16 hrs.
  • the reaction mixture was cooled to 20 °C, and NaBH 3 CN (10.51 mg, 167.29 ⁇ mol) was added.
  • the mixture was stirred at 20 °C for 2 hrs.
  • the mixture was concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (Column: Kromasil 100-5-C18 30*150 mm, mobile phase A: water (0.01%TFA) , mobile phase B: acetonitrile, 25 mL/min, gradient condition form 30%B to 70%) .
  • Step 1 Synthesis of 1- (4-chloro-3-fluorophenyl) -4- (dimethoxymethyl) piperidine
  • Step 2 ⁇ 4 Synthesis of compound 6: (S) -1- (5- ( (4- ( (1- (4-chloro-3-fluorophenyl) piperidin-4-yl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 7 The following compounds in Table 1 were prepared by the method of compound 4
  • Example 8 Preparation of compound 9: 1- (5- ( ( (S) -4- ( ( (1R, 4S) -4-cyclopropylcyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 Synthesis of methyl (1R, 4R) -4-formylcyclohexane-1-carboxylate
  • Step 2 Synthesis of methyl (1R, 4R) -4-vinylcyclohexane-1-carboxylate
  • Step 3 Synthesis of methyl (1R, 4R) -4-cyclopropylcyclohexane-1-carboxylate
  • Step 4 Synthesis of methyl ( (1R, 4R) -4-cyclopropylcyclohexyl) methanol
  • Step 5 Synthesis of (1R, 4R) -4-cyclopropylcyclohexane-1-carbaldehyde
  • Step 6 Synthesis of compound 9: 1- (5- ( ( (S) -4- ( ( (1R, 4S) -4-cyclopropylcyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • the crude product was purified by reversed-phase HPLC (Condition: 40%to 70%of phase B (Phase A: water (neutral) , Phase B: MeCN, Flow rate: 20 mL/min) and directly dry-freezing. Then the crude product was again purified by prep-TLC to give 1- (5- ( ( (S) -4- ( ( (1R, 4S) -4-cyclopropylcyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione (2.96 mg, 7.8%yield, 100%purity) as a white solid.
  • Example 9 The following compounds in Table 2 were prepared by the method of compound 6
  • Step 3 Synthesis of tert-butyl (S) -4- ( (3- ( (3-amino-3-oxopropyl) amino) benzo [d] isoxazol-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 4 Synthesis of tert-butyl (S) -4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzo [d] isoxazol-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 5 Synthesis of (S) -1- (5- ( (3-methylpiperazin-1-yl) methyl) benzo [d] isoxazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 6 Synthesis of Compound 16: (S) -6- (4- ( (4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzo [d] isoxazol-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidin-1-yl) nicotinonitrile
  • Step 1 Synthesis of tert-butyl (S) -4- (benzofuran-5-ylmethyl) -2-methylpiperazine-1-carboxylate
  • Step 2 Synthesis of tert-butyl (S) -4- ( (3-bromobenzofuran-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 3 Synthesis of tert-butyl (S) -4- ( (3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzofuran-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 4 Synthesis of (S) -3- (4-methoxybenzyl) -1- (5- ( (3-methylpiperazin-1-yl) methyl) benzofuran-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 5 Synthesis of 6- (4- (dimethoxymethyl) piperidin-1-yl) nicotinonitrile
  • Step 6 Synthesis of 6- (4-formylpiperidin-1-yl) nicotinonitrile
  • Step 7 Synthesis of (S) -6- (4- ( (4- ( (3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzofuran-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidin-1-yl) nicotinonitrile
  • the mixture was stirred at 50 °C for 2 hrs.
  • the reaction mixture was cooled to 20 °C, and NaBH 3 CN (28.5 mg, 454.0 ⁇ mol) was added.
  • the mixture was stirred at 20 °C for 1 hr.
  • the mixture was concentrated under reduced pressure.
  • Step 8 Synthesis of compound 17: (S) -6- (4- ( (4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) benzofuran-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidin-1-yl) nicotinonitrile
  • Step 5 Synthesis of tert-butyl (S) -4- ( (3- ( (3-amino-3-oxopropyl) amino) -6-fluorobenzo [d] isoxazol-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • the mixture was sprayed with N 2 for another 5 minutes and then stirred at 100 °C under microwave irradiation for 1 hr.
  • the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 2) .
  • the combined organic extracts were washed with brine (10 mL) , dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to afford the crude product, which was purified by flash silica gel chromatography ( 4 g Silica Flash Column, Eluent of 0 ⁇ 10%Methanol/Dichloromethane gradient @20 mL/min) .
  • Step 6 Synthesis of tert-butyl (S) -4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -6-fluorobenzo [d] isoxazol-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 7 Synthesis of (S) -1- (6-fluoro-5- ( (3-methylpiperazin-1-yl) methyl) benzo [d] isoxazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 8 Synthesis of compound 14: (S) -1- (6-fluoro-5- ( (4-isobutyl-3-methylpiperazin-1-yl) methyl) benzo [d] isoxazol-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 13 The following compounds in Table 3 were prepared by the method of compound 6 with the appropriate aldehyde.
  • Example 14 The following compounds in Table 4 were prepared by the method of compound 17 with the appropriate aldehyde
  • Example 15 The following compounds in Table 5 were prepared by the method of compound 20
  • Step 1 Synthesis of (S) -1- (2-fluoro-5- ( (4-isobutyl-3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • the NaBH 3 CN (19.5 mg, 310 ⁇ mol) was added to the mixture and stirred at 25°C for 1 hr.
  • the mixture was concentrated under reduced pressure, which was purified by flash silica gel chromatography ( 12 g Silica Flash Column, Eluent of 0 ⁇ 20%Methanol/Dichloromethane gradient @25 mL/min) .
  • Step 2 Synthesis of (S) -1- (2-fluoro-5- ( (4-isobutyl-3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 17 The following compounds in Table 6 were prepared by the method of compound 48
  • Step 1 Synthesis of 4- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridine
  • Step 2 Synthesis of 1-amino-4- ( ( (tert-butyldimethylsilyl) oxy) methyl) pyridin-1-ium; 2, 4-dinitrophenolate
  • Step 3 Synthesis of ethyl 5- ( ( (tert-butyldimethylsilyl) oxy) methyl) -2-methylpyrazolo [1, 5-a] pyridine-3-carboxylate
  • Step 5 Synthesis of 2-methylpyrazolo [1, 5-a] pyridine-5-carbaldehyde
  • Step 6 Synthesis of tert-butyl (S) -2-methyl-4- ( (2-methylpyrazolo [1, 5-a] pyridin-5-yl) methyl) piperazine-1-carboxylate
  • Step 7 Synthesis of tert-butyl (S) -4- ( (3-iodo-2-methylpyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 8 Synthesis of tert-butyl (S) -4- ( (3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-methylpyr azolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 9 Synthesis of (S) -3- (4-methoxybenzyl) -1- (2-methyl-5- ( (3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 10 Synthesis of (S) -1- (5- ( (4-isobutyl-3-methylpiperazin-1-yl) methyl) -2-methylpyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 11 Synthesis of compound 51 (S) -1- (5- ( (4-isobutyl-3-methylpiperazin-1-yl) methyl) -2-methylpyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 Synthesis of tert-butyl (3-chloropyridin-4-yl) carbamate
  • Step 2 Synthesis of tert-butyl N- (1-amino-3-chloro-pyridin-1-ium-4-yl) carbamate; 2, 4-dinitrophenolate
  • Step 3 Synthesis of ethyl 5- ( (tert-butoxycarbonyl) amino) -4-chloropyrazolo [1, 5-a] pyridine-3-carboxylate
  • Step 4 Synthesis of ethyl 5-amino-4-chloropyrazolo [1, 5-a] pyridine-3-carboxylate
  • Step 5 Synthesis of ethyl 4-chloro-5-iodopyrazolo [1, 5-a] pyridine-3-carboxylate
  • Step 6 Synthesis of 4-chloro-5-iodopyrazolo [1, 5-a] pyridine
  • Step 7 Synthesis of 4-chloro-5-iodo-3-nitropyrazolo [1, 5-a] pyridine
  • Step 8 Synthesis of 4-chloro-5-iodopyrazolo [1, 5-a] pyridin-3-amine
  • Step 9 Synthesis of ethyl (4-chloro-5-iodopyrazolo [1, 5-a] pyridin-3-yl) carbamate
  • Step 10 Synthesis of ethyl (4-chloro-5-vinylpyrazolo [1, 5-a] pyridin-3-yl) carbamate
  • Step 11 Synthesis of ethyl (4-chloro-5-formylpyrazolo [1, 5-a] pyridin-3-yl) carbamate
  • Step 12 Synthesis of tert-butyl (S) -4- ( (4-chloro-3- ( (ethoxycarbonyl) amino) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazine-1-carboxylate
  • Step 14 Synthesis of (S) -1- (4-chloro-5- ( (3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 15 Synthesis of (S) -1- (4-chloro-5- ( (4-isobutyl-3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 Synthesis of 2- (4- (dimethoxymethyl) piperidin-1-yl) -5-methylpyrimidine
  • Step 3 Synthesis of (S) -1- (2-fluoro-5- ( (3-methyl-4- ( (1- (5-methylpyrimidin-2-yl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 20 The compounds in Table 7 were prepared by the method of compound 53
  • Step 1 Synthesis of 4- (dimethoxymethyl) -1- (1-methyl-1H-pyrazol-3-yl) piperidine
  • Step 3 Synthesis of 3- (2-fluoro-5- ( ( (S) -3-methyl-4- ( (1- (1-methyl-1H-pyrazol-3-yl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -1- (4-methoxybenzyl) piperidine-2, 6-dione
  • Step 4 Synthesis of 3- (2-fluoro-5- ( ( (S) -3-methyl-4- ( (1- (1-methyl-1H-pyrazol-3-yl) piperidin-4-yl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) piperidine-2, 6-dione
  • Example 22 The following compounds in Table 8 were prepared according to the procedures described for the compound 85 using the appropriate heteroaryl fragments.
  • Step 1 Synthesis of 4- ( ( (tert-butyldimethylsilyl) oxy) methyl) cyclohexan-1-one
  • Step 2 Synthesis of 4- ( ( (tert-butyldimethylsilyl) oxy) methyl) cyclohex-1-en-1-yl (1, 1, 1, 2, 3, 3, 4, 4-octafluoro-4l3-butan-2-yl) -l2-fluoranesulfonate
  • Step 3 Synthesis of 3- (4- ( ( (tert-butyldimethylsilyl) oxy) methyl) cyclohex-1-en-1-yl) -1-methyl-1H-pyrazole
  • Step 4 Synthesis of 3- (4- ( ( (tert-butyldimethylsilyl) oxy) methyl) cyclohexyl) -1-methyl-1H-pyrazole
  • Step 5 Synthesis of (4- (1-methyl-1H-pyrazol-3-yl) cyclohexyl) methanol
  • Step 6 Synthesis of 4- (1-methyl-1H-pyrazol-3-yl) cyclohexane-1-carbaldehyde
  • Step 7 Synthesis of (S) -1- (2-fluoro-5- ( (3-methyl-4- ( (4- (1-methyl-1H-pyrazol-3-yl) cyclohexyl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 8 Synthesis of (S) -1- (2-fluoro-5- ( (3-methyl-4- ( (4- (1-methyl-1H-pyrazol-3-yl) cyclohexyl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 9 Chiral separation of Compound 99 and 100
  • Example 24 The compounds in Table 9 were prepared according to the procedures of the compound 98.
  • Step 1 Synthesis of methyl (1r, 4r) -4- (methoxy (methyl) carbamoyl) cyclohexane-1-carboxylate
  • Step 2 Synthesis of (1r, 4r) -4- (hydroxymethyl) -N-methoxy-N-methylcyclohexane-1-carboxamide
  • Step 3 Synthesis of (1r, 4r) -4- ( ( (tert-butyldimethylsilyl) oxy) methyl) -N-methoxy-N-methylcyclohexane-1-carboxamide
  • Step 4 Synthesis of 1- ( (1r, 4r) -4- ( ( (tert-butyldimethylsilyl) oxy) methyl) cyclohexyl) ethan-1-one
  • Step 5 Synthesis of (E) -1- ( (1r, 4r) -4- ( ( (tert-butyldimethylsilyl) oxy) methyl) cyclohexyl) -3- (dimethylamino) prop-2-en-1-one
  • Step 6 Synthesis of ( (1r, 4r) -4- (1-methyl-1H-pyrazol-3-yl) cyclohexyl) methanol and ( (1r, 4r) -4- (1-methyl-1H-pyrazol-5-yl) cyclohexyl) methanol
  • Step 7 Synthesis of (1r, 4r) -4- (1-methyl-1H-pyrazol-3-yl) cyclohexane-1-carbaldehyde and (1r, 4r) -4- (1-methyl-1H-pyrazol-5-yl) cyclohexane-1-carbaldehyde
  • Step 8 Synthesis of 1- (2-fluoro-5- ( ( (S) -3-methyl-4- ( ( (1r, 4S) -4- (1-methyl-1H-pyrazol-3-yl) cyclohexyl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropy rimidine-2, 4 (1H, 3H) -dione and 1- (2-fluoro-5- ( ( (S) -3-methyl-4- ( ( (1r, 4S) -4- (1-methyl-1H-pyrazol-5-yl) cyclohexyl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropy rimidine-2, 4 (1H, 3H) -dione and 1- (2-fluoro-5- (
  • Step 9 Synthesis of 1- (2-fluoro-5- ( ( (S) -3-methyl-4- ( ( (1*r, 4*S) -4- (1-methyl-1H-pyrazol-3-yl) cyclohexyl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 26 preparation of compound 131: (S) -1- (5- ( (4- (4- (1-ethyl-1H-pyrazol-3-yl) cyclohexyl) -3-methylpiperazin-1-yl) methyl) -2-fluoropyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 2 Synthesis of 1-ethyl-3- (1, 4-dioxaspiro [4.5] dec-7-en-8-yl) -1H-pyrazole
  • Step 3 Synthesis of 1-ethyl-3- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole
  • Step 4 Synthesis of 4- (1-ethyl-1H-pyrazol-3-yl) cyclohexan-1-one
  • Step 5 Synthesis of (S) -1- (5- ( (4- (4- (1-ethyl-1H-pyrazol-3-yl) cyclohexyl) -3-methylpiperazin-1-yl) methyl) -2 -fluoropyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 6 Synthesis of (S) -1- (5- ( (4- (4- (1-ethyl-1H-pyrazol-3-yl) cyclohexyl) -3-methylpiperazin-1-yl) methyl) -2 -fluoropyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 27 The following compounds in Table 10 were prepared according to the procedures described for the Compound 131 using the appropriate ketone derivatives.
  • Example 28 preparation of compound 140: 1- (2-fluoro-5- ( ( (S) -4- ( ( (1*r, 4*S) -4- (4-fluoro-1H-pyrazol-1-yl) cyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H)-dione
  • Step 1 Synthesis of methyl (1r, 4r) -4- (4-fluoro-1H-pyrazol-1-yl) cyclohexane-1-carboxylate
  • Step 2 Synthesis of ( (1r, 4r) -4- (4-fluoro-1H-pyrazol-1-yl) cyclohexyl) methanol
  • Step 3 Synthesis of (1r, 4r) -4- (4-fluoro-1H-pyrazol-1-yl) cyclohexane-1-carbaldehyde
  • Step 5 Synthesis of 1- (2-fluoro-5- ( ( (S) -4- ( ( (1r, 4S) -4- (4-fluoro-1H-pyrazol-1-yl) cyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 6 Synthesis of 1- (2-fluoro-5- ( ( (S) -4- ( ( (1r, 4S) -4- (4-fluoro-1H-pyrazol-1-yl) cyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 29 The following compounds in Table 11 were prepared according to the procedures of the compound 140.
  • Step 2 Synthesis of 4-methyl-1- (1, 4-dioxaspiro [4.5] decan-8-yl) -1H-pyrazole
  • Step 3 Synthesis of 4- (4-methyl-1H-pyrazol-1-yl) cyclohexan-1-one
  • Step 4 Synthesis of (S) -1- (2-fluoro-5- ( (3-methyl-4- (4- (4-methyl-1H-pyrazol-1-yl) cyclohexyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) -3- (4-methoxybenzyl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 5 Synthesis of (S) -1- (2-fluoro-5- ( (3-methyl-4- (4- (4-methyl-1H-pyrazol-1-yl) cyclohexyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 1 Synthesis of tert-butyl (S) -4- ( (4- ( (2-fluoro-3- (3- (4-methoxybenzyl) -2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) pyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidine-1-carboxylate
  • Step 2 Synthesis of (S) -1- (2-fluoro-5- ( (3-methyl-4- (piperidin-4-ylmethyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 3 Synthesis of tert-butyl (S) -4- ( (4- ( (3- (2, 4-dioxotetrahydropyrimidin-1 (2H) -yl) -2-fluoropyrazolo [1, 5-a] pyridin-5-yl) methyl) -2-methylpiperazin-1-yl) methyl) piperidine-1-carboxylate
  • Step 4 Synthesis of (S) -1- (2-fluoro-5- ( (3-methyl-4- (piperidin-4-ylmethyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Step 5 Synthesis of (S) -1- (2-fluoro-5- ( (4- ( (1- (isopropylsulfonyl) piperidin-4-yl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione
  • Example 32 The following compounds in Table 12 were prepared according to the procedures of the compound 162.
  • HT-1080 cell line was purchased from ATCC (Cat#CCL-121) , which was then engineered to stably overexpress GSPT (1-138) /G575N mutant and HiBiT tagged WIZ isoform 3.
  • Cells were cultured in DMEM medium supplemented with 10%heat-inactivated FBS, 1X sodium pyruvate, 1X non-essential amino acids, 1X glutamine, 100 U/ml penicillin, and 100 ug/mL streptomycin.
  • WIZ degradation assay about 10,000 engineered HT-1080 cells in 35 l culture medium were seeded into 384-well plates (Cat#3764, Corning) , pre-spotted with test compounds using the Echo 650 liquid handler (Beckman) .
  • the half-log dose-response-curve (DRC) typically has 10 points with the highest concentration at 10 M, and the lowest concentration at 0.316 nM.
  • Assay plates were incubated at 37 °C with 5%CO 2 for 20 hrs. WIZ degradation was then assessed using the Nano-Glo HiBiT Lytic Detection Reagent according to the manufacturer’s instructions. Luminescence was measured on a Pherastar microplate reader (BMG Labtech) .
  • A Y min (lowest WIZ level normalized to DMSO control in response to compound treatment, as determined by curve fit)
  • D max represented the maximum percentage of WIZ degradation that could be achieved by a compound at its highest treatment concentration.
  • Reference 1 is (S) -1- (5- ( (4-isobutyl-3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione;
  • Reference 2 is (S) -1- (5- ( (4- ( (4, 4-difluorocyclohexyl) methyl) -3-methylpiperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione;
  • Reference 3 is (S) -1- (5- ( (3-methyl-4- ( (tetrahydro-2H-pyran-4-yl) methyl) piperazin-1-yl) methyl) pyrazolo [1, 5-a] pyridin-3-yl) dihydropyrimidine-2, 4 (1H, 3H) -dione.
  • Primary human CD34 + cells were purchased from STEMCELL Technologies Inc. The cells were isolated from G-CSF mobilized peripheral blood leukapheresis samples obtained from healthy donors. Erythroid differentiation was performed using a 2-phase liquid culture system. During the first 6 days (first phase) , cells were expanded in StemSpan TM SFEM II hematopoietic medium (STEMCELL Technologies Inc. ) containing rhIL-3 (Peprotech, Inc. ) , rhIL-6 (Peprotech, Inc. ) , rhSCF (Peprotech, Inc. ) , rhFlt3L (Peprotech, Inc.
  • the cells were washed with Cyto-Fast TM Perm Wash solution and then stained with FITC-conjugated anti-HbF (Invitrogen) antibody for 30 minutes at room temperature in the dark. Finally, the cells were washed with Cyto-Fast TM Perm Wash solution and resuspended in stain buffer, followed by flow cytometry analysis using a NovoCyte Quanteon flow cytometer (Agilent) . Data analysis was performed using the NovoExpress software (Agilent) .
  • Example 53 The pharmacokinetic study after single intravenous and oral administration in mice
  • Sample collection and preparation After intravenous injection or oral administration of test compounds, blood samples were collected and collection time was recorded. After collection, the blood sample was immediately transferred into a labeled centrifuge tube containing K2-EDTA, followed by centrifugation and plasma collection. The plasma was then transferred into a pre-cooled centrifuge tube, quickly frozen on dry ice, and stored in an ultra-low temperature refrigerator at -70 ⁇ 10°C until the LC-MS/MS analysis was performed.
  • Pharmacokinetic data analysis The pharmacokinetic software was used to process the plasma drug concentration data of the compound in a non-compartmental model.
  • the peak concentration (C max ) , peak time (T max ) and quantifiable end time can be directly obtained from the plasma concentration-time diagram.
  • the log-linear trapezoidal method was used to calculate the following pharmacokinetic parameters: half-life (T 1/2 ) , apparent volume of distribution (V ss ) and clearance (Cl) , and the area under the time-plasma concentration curve (AUC 0-inf ) from the 0 point to the end point.

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Abstract

La présente invention concerne des composés polycycliques contenant de la dihydropyrimidine -2, 4 (1H, 3H)-dione, ou des sels pharmaceutiquement acceptables de ceux-ci, et des compositions associées qui sont efficaces pour réduire ou moduler des niveaux d'expression de protéine à motifs doigt de zinc largement espacés (WIZ) et/ou induire l'expression d'hémoglobine foetale (HbF), et concerne également des procédés de préparation de ceux-ci et leur utilisation dans le traitement de sujets en ayant besoin.
PCT/CN2024/099076 2023-06-15 2024-06-13 Dérivés polycycliques contenant de la dihydropyrimidine-2, 4 (1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation Ceased WO2024255810A1 (fr)

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KR1020267001182A KR20260022448A (ko) 2023-06-15 2024-06-13 디히드로피리미딘-2,4(1h,3h)-디온을 함유하는 폴리시클릭 유도체 및 이의 약학적 조성물, 이의 제조 방법 및 이의 용도
CN202480040029.4A CN121794269A (zh) 2023-06-15 2024-06-13 含二氢嘧啶-2,4(1h,3h)-二酮的多环衍生物及其药物组合物、其制备方法和其用途
AU2024302642A AU2024302642A1 (en) 2023-06-15 2024-06-13 Dihydropyrimidine-2, 4 (1h, 3h) -dione-containing polycyclic derivatives and pharmaceutical composition thereof, preparation method thereof and use thereof
EP24822758.9A EP4727940A1 (fr) 2023-06-15 2024-06-13 Dérivés polycycliques contenant de la dihydropyrimidine-2, 4 (1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation
PCT/CN2025/099373 WO2025256460A1 (fr) 2023-06-15 2025-06-05 Dérivés polycycliques contenant de la dihydropyrimidine-2,4(1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation
MX2025015193A MX2025015193A (es) 2023-06-15 2025-12-15 Derivados policiclicos que contienen dihidropirimidina-2,4(1h,3h)-diona y sus composiciones farmaceuticas, metodos de preparacion y usos
IL325349A IL325349A (en) 2023-06-15 2025-12-15 Polycyclic derivatives containing dihydropyrimidine-2, 4(1h, 3h) -dione, their pharmaceutical composition, method of preparation and use thereof

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PCT/CN2025/099373 Pending WO2025256460A1 (fr) 2023-06-15 2025-06-05 Dérivés polycycliques contenant de la dihydropyrimidine-2,4(1h, 3h)-dione et composition pharmaceutique associée, leur procédé de préparation et leur utilisation

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WO2021053555A1 (fr) * 2019-09-16 2021-03-25 Novartis Ag Agents de dégradation de colle et leurs procédés d'utilisation
WO2021124172A1 (fr) * 2019-12-18 2021-06-24 Novartis Ag Dérivés de 3-(5-méthoxy-1-oxoisoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
WO2022195355A1 (fr) * 2021-03-15 2022-09-22 Novartis Ag Dérivés de benzisoxazole et leurs utilisations
WO2022195454A1 (fr) * 2021-03-15 2022-09-22 Novartis Ag Dérivés de pyrazolopyridine et leurs utilisations
WO2022268229A1 (fr) * 2021-06-25 2022-12-29 和径医药科技（上海）有限公司 Inhibiteur de protéine ou agent de dégradation, composition pharmaceutique le contenant et utilisation pharmaceutique
WO2023023531A1 (fr) * 2021-08-20 2023-02-23 Biotheryx, Inc. Agents de dégradation du récepteur des œstrogènes, compositions pharmaceutiques et applications thérapeutiques

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CN116940571A (zh) * 2021-03-15 2023-10-24 诺华股份有限公司 苯并异噁唑衍生物及其用途
CN116802182A (zh) * 2021-03-15 2023-09-22 诺华股份有限公司 吡唑并吡啶衍生物及其用途

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Publication number Priority date Publication date Assignee Title
WO2021053555A1 (fr) * 2019-09-16 2021-03-25 Novartis Ag Agents de dégradation de colle et leurs procédés d'utilisation
WO2021124172A1 (fr) * 2019-12-18 2021-06-24 Novartis Ag Dérivés de 3-(5-méthoxy-1-oxoisoindolin-2-yl)pipéridine-2,6-dione et leurs utilisations
WO2022195355A1 (fr) * 2021-03-15 2022-09-22 Novartis Ag Dérivés de benzisoxazole et leurs utilisations
WO2022195454A1 (fr) * 2021-03-15 2022-09-22 Novartis Ag Dérivés de pyrazolopyridine et leurs utilisations
WO2022268229A1 (fr) * 2021-06-25 2022-12-29 和径医药科技（上海）有限公司 Inhibiteur de protéine ou agent de dégradation, composition pharmaceutique le contenant et utilisation pharmaceutique
WO2023023531A1 (fr) * 2021-08-20 2023-02-23 Biotheryx, Inc. Agents de dégradation du récepteur des œstrogènes, compositions pharmaceutiques et applications thérapeutiques

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