WO2017062688A1 - Inhibiteurs de la voie de signalisation wnt et leurs applications thérapeutiques - Google Patents

Inhibiteurs de la voie de signalisation wnt et leurs applications thérapeutiques Download PDF

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WO2017062688A1
WO2017062688A1 PCT/US2016/055851 US2016055851W WO2017062688A1 WO 2017062688 A1 WO2017062688 A1 WO 2017062688A1 US 2016055851 W US2016055851 W US 2016055851W WO 2017062688 A1 WO2017062688 A1 WO 2017062688A1
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substituted
unsubstituted
alkyl
independently selected
groups
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PCT/US2016/055851
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Xiaohu Zhang
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Suzhou Yunxuan Yiyao Keji Youxian Gongsi
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Priority claimed from CN201510645986.2A external-priority patent/CN105254613A/zh
Priority claimed from CN201610670828.7A external-priority patent/CN107759584B/zh
Priority claimed from CN201610850357.8A external-priority patent/CN107286135B/zh
Priority claimed from CN201610850358.2A external-priority patent/CN107286136B/zh
Application filed by Suzhou Yunxuan Yiyao Keji Youxian Gongsi filed Critical Suzhou Yunxuan Yiyao Keji Youxian Gongsi
Priority to KR1020187013073A priority Critical patent/KR20180061363A/ko
Priority to EP16854369.2A priority patent/EP3359154B1/fr
Priority to JP2018518629A priority patent/JP6853819B2/ja
Priority to US15/766,799 priority patent/US10450300B2/en
Publication of WO2017062688A1 publication Critical patent/WO2017062688A1/fr
Priority to US16/653,217 priority patent/US20200048223A1/en

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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention generally relates to heterocyclic compounds and, more particularly, relates to novel heterocyclic compounds that are useful in therapies targeting the Wnt signaling pathway mediated diseases, such as cancer, in mammals.
  • the Wnt signaling pathway has critical roles in developmental pathways, including regulatory roles in cell proliferation, tissue patterning, and cell fate, migration,
  • the canonical Wnt signaling pathway is activated by Wnt proteins that interact with seven-pass transmembrane receptors of the Frizzled (Fzd) family and single-pass transmembrane co-receptors, such as lipoprotein receptor-related protein 5/6 (LRP5/6).
  • Wnt proteins that interact with seven-pass transmembrane receptors of the Frizzled (Fzd) family and single-pass transmembrane co-receptors, such as lipoprotein receptor-related protein 5/6 (LRP5/6).
  • Such interaction activates the Wnt signaling pathway by recruiting and activating the Dishevelled (Dvl) protein, which, in turn, silences glycogen synthase kinase 3 ⁇ (GSK3 ⁇ ) within a destructive complex formed by adenomatous polyposis coli (APC) protein, GSK3 ⁇ , Axin, and a priming kinase for ⁇ -catenin called casein kinase 1 ⁇ (CK1 ⁇ ).
  • the destructive complex can phosphorylate ⁇ -catenin for its degradation.
  • cytoplasmic ⁇ -catenin can be stabilized and accumulated in the presence of lymphoid enhancing factor/T-cell factor (LEF/TCF) transcription factors so that ⁇ -catenin can be
  • Cancer (2004) 109:106-111 decrease of neural precursor cells (Chenn and Walsh, Science (2002) 297:365-9), pathogenesis of sporadic medulloblastoma (Dahmen et al., Cancer Res. (2001) 61:7039-43), malignant proliferation of cancer cells due to disruption of Wnt signaling pathway in stem and progenitor cells (Reya and Clevers, Nature (2005) 434:843-850).
  • the present invention provides compounds of Formula I:
  • A is A1, A2, A3 or A4;
  • U is U1, U2, U3 or U4;
  • L is L1, L2, or L3;
  • Q is Q1, Q2, Q3 or Q4;
  • Z is Z1, Z2, Z3 or Z4;
  • X 1 to X 7 are independently selected from N and C ⁇ R 13 ;
  • X 13 and X 15 are independently O, N, S or
  • U1 is , wherein X 8 to X 10
  • G 1 and G 2 are independently selected from N and C; 3
  • V 1 and V 2 are independently selected from N, O, S and C ⁇ R 15 ;
  • V 5 connects with V 2 ;
  • U2 is C 6 -C 10 aryl, 5-12 membered heteroaryl, 11-13 membered heterocyclophenyl or 10-13 membered heterocycloheteroaryl, wherein heterocyclo and heteroaryl comprises 1 to 4 heteroatoms independently selected from N, O and S; and
  • C 6 -C 10 aryl, 5-12 membered heteroaryl, 11-13 membered heterocyclophenyl and 10- 13 membered heterocycloheteroaryl are unsubstituted or substituted with 1 to 4 R 6a groups;
  • U3 is ⁇ OR 14b , ⁇ NR 14b R 15b , C 6 -C 12 aryl unsubstituted or substituted with 1-6 R 13b group, 5-14 membered heteroaryl unsubstituted or substituted with 1-6 R 13b group, 11-13 membered heterocyclophenyl unsubstituted or substituted with 1-6 R 13b group, 10-13 membered heterocycloheteroaryl unsubstituted or substituted with 1-6 R 13b group, C 2 -C 8 alkenyl substituted with 5-6 membered aryl or heteroaryl, C 2 -C 8 alkynyl substituted with 5-6 membered aryl or
  • heteroaryl or unsubstituted or substituted with 1 to 2 R 13b groups, wherein heterocyclo and heteroaryl comprises 1 to 4 heteroatoms independently selected from N, O and S; and
  • X 11 is N or C ⁇ R 13b ;
  • X 10 are independently selected from N and C ⁇ R 15c ;
  • G 1 and G 2 are independently selected from N and C; 4
  • V 1 and V 2 are independently selected from N, O, S and C ⁇ R 16c ;
  • V 3 , V 4 ⁇ V 5 or V 4 V 5 , wherein V 3 to V 5 are independently selected from N, O, S and C ⁇ R 17c , wherein V 4 connects with V 1 ; and
  • V 5 connects with V 2 ;
  • Y 2 is blank, ⁇ O ⁇ , ⁇ S ⁇ , ⁇ N(R 18b ) ⁇ or ⁇ C(R 18b )(R 19b ) ⁇ ;
  • L3 is ⁇ C(R 2c )(R 3c ) ⁇ or ⁇ NHCH 2 CH 2 ⁇ ;
  • Q1 is C 6 -C 10 arylene or 5-12 membered heteroarylene, wherein 5-12 membered heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S; and
  • C 6 -C 10 aryl and 5-12 membered heteroarylene are unsubstituted or substituted with 1 to 4 R 17 groups;
  • Q2 is C 6 -C 10 arylene or 5-10 membered heteroarylene, wherein 5-10 membered heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S; and
  • C 6 -C 10 arylene and 5-10 membered heteroarylene are unsubstituted or substituted with 1 to 4 R 4a groups;
  • Q3 is C 6 -C 12 arylene unsubstituted or substituted with 1-6 R 6b group, 5-14 membered heteroarylene unsubstituted or substituted with 1-6 R 6b group, C 3 -C 6 cycloalkylene unsubstituted or substituted with 1-6 R 6b group, C 3 -C 6 heterocylene unsubstituted or
  • heterocyclene and heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S;
  • X 12 is N or C ⁇ R 6b ; 5
  • Q4 is C 6 -C 10 arylene or 5-12 membered heteroarylene, wherein 5-12 membered heteroarylene comprises 1 to 4 heteroatoms independently selected from N, O and S; and
  • C 6 -C 10 arylene and 5-12 membered heteroarylene are unsubstituted or substituted with 1 to 4 R 5c groups;
  • Z1 is ⁇ CN, C 6 aryl, 5-6 membered heteroaryl, or , wherein 5-6 membered heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O and S;
  • C 6 aryl and 5-6 membered heteroaryl are unsubstituted or substituted with 1 to 3 R 18 groups;
  • Y 1 is O or NR 20 ;
  • q 0, 1, 2, or 3;
  • Z2 is H, ⁇ CN, halide, ⁇ OH, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkylsulfonyl, C 1 -C 8 acyl, aminoacyl, C 1 -C 8 acylamino, C 1 -C 8 alkylcarbamoylamino, C1-C8 alkoxycarbamoyl, C1-C8 alkylsulfonamido, C1-C8 alkylaminosulphonyl, C 1 -C 8 alkoxy, C 2 -C 8 alkoxyacyl, phenyl, 5-6 membered heteroaryl, or 5-7 membered heterocyclo, wherein 5-6 membered heteroaryl and 5-7 membered heterocyclo comprise one or more hetero atoms independently selected from N, O and S; and
  • phenyl, 5-6 membered heteroaryl and 5-7 membered heterocycle are unsubstituted or substituted with 1 to 3 R 5a groups;
  • Z3 is H, ⁇ CN, halide, ⁇ OH, C 1 -C 8 alkyl unsubstituted or substituted with 1 to 3 R 12b groups, C 3 -C 8 cycloalkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkylsulfonyl, C 1 -C 8 acyl, aminoacyl, C 1 -C 8 acylamino, C 1 -C 8 alkylcarbamoylamino, C 1 -C 8
  • alkoxycarbamoyl C 1 -C 8 alkylsulfonamido, C 1 -C 8 alkylaminosulphonyl, C 1 -C 8 alkoxy, C 2 -C 8 alkoxyacyl, ⁇ N(R 7b )(R 8b ) unsubstituted or substituted with 1 to 3 R 12b groups, phenyl unsubstituted or substituted with 1 to 3 R 9b groups, 5-6 membered heteroaryl unsubstituted or substituted with 1 to 3 R 10b groups, or 5-7 membered heterocyclo unsubstituted or substituted with 1 to 3 R 11b groups, wherein 5-6 membered heteroaryl 6
  • 5-7 membered heterocyclo comprises 1-3 hetero atoms independently selected from N, O and S;
  • Z4 is ⁇ CN, C 6 aryl, 5-6 membered heteroaryl, or , wherein 5- 6 membered heteroaryl comprises 1 to 3 heteroatoms independently selected from N, O and S;
  • C 6 aryl and 5-6 membered heteroaryl are unsubstituted or substituted with 1 to 3 R 6c groups;
  • Y 3 is O or NR 8c ;
  • q 0, 1, 2, or 3;
  • R 1 to R 3 are independently selected from H and C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is unsubstituted or substituted with 1 to 3 halide, ⁇ CN, ⁇ OH, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or C 1 -C 3 alkoxy groups;
  • R 4 is H, halide, ⁇ CN, ⁇ OH, ⁇ NO 2 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl and C 1 -C 6 alkoxy are unsubstituted or substituted with 1 to 3 halide;
  • R 5 and R 6 are independently selected from H, halide, ⁇ CN, ⁇ OH, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy, wherein C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl and C 1 -C 6 alkoxy are unsubstituted or substituted with 1 to 3 halide;
  • R 9 to R 12 are independently selected from H, C 1 -C 6 alkyl
  • R 13 is H, halide, ⁇ CN, ⁇ OH, amino, ⁇ NO 2 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio or 1-pyrrolidino, wherein amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy are unsubstituted or substituted with 1 to 3 halide, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl groups;
  • R 14 to R 17 are independently selected from H, halide, ⁇ CN, ⁇ OH, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy and C 1 -C 6 alkylthio, wherein amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy are unsubstituted or substituted with 1 to 3 halide, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl groups; 7
  • R 18 is H, halide, ⁇ CN, ⁇ OH, amino, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy, wherein amino, C 1 -C 6 alkyl and C 1 -C 6 alkoxy are unsubstituted or substituted with 1 to 3 halide, C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl groups;
  • R 19 and R 20 are independently selected from H and C 1 -C 3 alkyl, or R 19 and R 20 together, with adjacent atoms they attached to, form a cyclic structure;
  • R 4a , R 5a and R 6a are independently selected from halide, ⁇ CN, and ⁇ OH, or R 4a , R 5a and R 6a are independently selected from C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 alkylsulfonyl, C1-C8 acyl, aminoacyl, C1-C8 acylamino, C 1 -C 8 alkylcarbamoylamino, C 1 -C 8 alkoxycarbamoyl, C 1 -C 8
  • alkylsulfonamido C 1 -C 8 alkylaminosulphonyl, C 2 -C 8 alkoxyacyl, and 3-8 membered heterocycle, all of which are unsubstituted or substituted with 1-3 halide, ⁇ OH, ⁇ CN, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl or C 3 -C 8 cycloalkyl groups, wherein 3-8 membered heterocycle comprises one or more hetero atoms from N, O or S;
  • R 2m is H, deuterium, tritium, halide, ⁇ OH, ⁇ CN, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl or C 1 - C 8 alkoxy;
  • R 2b and R 3b are independently selected from H, C 1 -C 6 alkyl unsubstituted or substituted with 1-3 groups selected from halide, ⁇ CN, ⁇ OH, C 1 -C 6 alkyl, C 3 -C 5 cycloalkyl and C 1 -C 3 alkoxy;
  • R 4b and R 5b are independently selected from H, halide, ⁇ CN, amino, C 1 -C 8 alkyl, C 3 - C 8 cycloalkyl, C 1 -C 8 alkoxy, and C 1 -C 3 alkylamino;
  • R 6b is H, halide, ⁇ CN or ⁇ OH, or R 6b is selected from amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and C 1 -C 3 alkylamino, all of which are unsubstituted or substituted with 1-3 halide, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl groups;
  • R 7b and R 8b are independently selected from H, C 1 -C 8 alkyl and C 3 -C 8 cycloalkyl, the latter two of which are unsubstituted or substituted with 1-3 R 12b , or R 7 and R 8 together, with adjacent atoms they attached to, form a cyclic structure;
  • R 9b and R 10b are independently selected from H, halide, ⁇ CN and ⁇ OH, or R 9b and R 10b are independently selected from amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkoxy, all of which are unsubstituted or substituted with 1-3 halide, C 1 -C 3 alkyl, or C 3 -C 6 cycloalkyl groups;
  • R 11b is H, halide, ⁇ CN, ⁇ OH, amino, C 1 -C 6 alkyl unsubstituted or substituted with halide, C 3 -C 6 cycloalkyl, oxo, or C 1 -C 6 alkoxy;
  • R 12b is H, ⁇ CN, ⁇ OH, amino, C1-C6 alkyl unsubstituted or substituted with halide, C3- C 6 cycloalkyl, oxo, or C 1 -C 6 alkoxy;
  • R 13b is H, halide, ⁇ CN, ⁇ OH, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 2 - C 6 alkylcarbamoylamino, C 2 -C 6 alkoxycarbamoyl, C 1 -C 3 alkylsulphonyl,
  • R 14b and R 15b are independently selected from H, C 3 -C 6 cycloalkyl unsubstituted or substituted with 1 to 3 R 20b groups, C 1 -C 6 alkyl unsubstituted or substituted with 1 to 3 R 20b groups, 5-6 membered aryl unsubstituted or substituted with 1 to 3 R 20b groups, 5-6 membered heteroaryl unsubstituted or substituted with 1 to 3 R 20b groups, and 5-6 membered heterocyclo unsubstituted or substituted with 1 to 3 R 20b groups, wherein 5-6 membered heteroaryl and 5-7 membered heterocyclo comprise 1 to 3 hetero atoms independently selected from N, O and S, or R 14b and R 15b together, with adjacent atoms they attached to, form a cyclic structure;
  • R 16b to R 19b are independently selected from H and C 1 -C 6 alkyl unsubstituted or substituted with halide;
  • R 20b is H, ⁇ CN, ⁇ OH, amino, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, 5-6 membered aryl, or 5-6 membered heteroaryl, wherein 5-6 membered heteroaryl comprises 1 to 3 hetero atoms independently selected from N, O and S;
  • R 21b is H or C 1 -C 6 alkyl
  • R 2c and R 3c are independently selected from H and C 1 -C 6 alkyl unsubstituted or substituted with 1-3 halide;
  • R 4c is H, halide, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or C 1 -C 3 alkoxy;
  • R 5c and R 6c are independently selected from H, halide, ⁇ CN, ⁇ OH, amino, C 1 -C 6 alkyl unsubstituted or substituted with 1-3 halide, C 3 -C 5 cycloalkyl, and C 1 -C 6 alkoxy;
  • R 7c and R 8c are independently selected from H and C 1 -C 6 alkyl, or R 7c and R 8c together, with adjacent atoms they attached to, form a cyclic structure;
  • R 9c to R 14c are independently selected from H, C 1 -C 6 alkyl and ⁇ CF 3 ;
  • R 15c to R 17c are independently selected from H, halide, ⁇ CN, ⁇ OH, amino, C 1 -C 6 alkyl unsubstituted or substituted with 1-3 halide, C 3 -C 5 cycloalkyl, and C 1 -C 6 alkoxy.
  • the compound of Formula I comprises Q which is
  • Q 1 to Q 10 are independently N or C ⁇ R 17 .
  • the compound of Formula I comprises A which is
  • the compound of Formula I comprises U which is
  • the compound of Formula I comprises U which is selected from:
  • the compound of Formula I comprises Q which is selected
  • the compound of Formula I comprises Z which is selected from:
  • the compound of Formula I comprises Q which is selected from:
  • the compound of Formula I comprises Z which is selected from:
  • the compound of Formula I comprises U which is selected from:
  • the compound of Formula I comprises Z which is
  • O , or Z is selected from:
  • the compound of Formula I comprises A which is selected from:
  • herein provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
  • herein provides a method for regulating the Wnt signaling pathway and/or treating a Wnt- mediated disorder in a mammal suffering therefrom.
  • the method comprises administrating to a mammalian subject a therapeutically effective amount of at least one compound of formula I, or a pharmaceutical composition thereof, and optionally in combination with a second therapeutic agent.
  • the method can treat a cell proliferative disorder selected from the group consisting of systemic sclerosis, skin fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, liver fibrosis, drug-induced fibrosis, radiation-induced fibrosis, colorectal cancer, breast cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, non-small cell lung cancer, gastric cancer, pancreatic cancer, leukemia, lymphoma, neuroblastoma, retinoblastoma, sarcoma, osteosarcoma, chondosarcoma, Ewing's sarcoma, rhabdomysarcoma, brain tumor, Wilms’ tumor, basal cell carcinoma, melanoma, head and neck cancer, cervical cancer and prostate cancer.
  • a cell proliferative disorder selected from the group consisting of systemic sclerosis, skin fibrosis, idiopathic pulmonary fibro
  • FIG.1 depicts the IC50 curve of compound A-12 of the present invention in the primary assay
  • FIG.2 depicts the IC50 curve of compound A-36 of the present invention in the primary assay
  • FIG.3 depicts the IC50 curve of compound A-100 of the present invention in the primary assay
  • FIG.4 depicts the IC50 curve of compound A-103 of the present invention in the primary assay
  • FIG.5 depicts the IC50 curve of compound A-166 of the present invention in the primary assay
  • FIG.6 depicts the IC50 curve of compound A-168 of the present invention in the primary assay
  • FIG.7 depicts the IC50 curve of compound A-194 of the present invention in the primary assay.
  • FIG.8 depicts the IC50 curve of compound A-198 of the present invention in the primary assay.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon.
  • Alkyl groups include groups having from 1 to 8 carbon atoms (C 1-8 alkyl), from 1 to 6 carbon atoms (C 1-6 alkyl) and from 1 to 4 carbon atoms (C 1-4 alkyl), including, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl.
  • a substituent of an alkyl group is specifically indicated.
  • “cyanoalkyl” refers to an alkyl group substituted with at least one cyano substituent.
  • Alkenyl refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include C 2-8 alkenyl, C 2-6 alkenyl and C2-4 alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, including, for example, ethenyl, allyl or isopropenyl. "Alkynyl” refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a triple bond. Alkynyl groups include C 2-8 alkynyl, C 2-6 alkynyl and C 2-4 alkynyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • a "cycloalkyl” is a group that comprises one or more saturated rings in which all ring members are carbon, including, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl. Cycloalkyl groups do not comprise an aromatic ring or a heterocyclic ring. Certain cycloalkyl groups are C 3-7 cycloalkyl, in which the cycloalkyl group contains a single ring having from 3 to 7 ring members, all of which are carbon.
  • A“cycloalkenyl” is a group that comprises one or more unsaturated rings in which all ring members are carbon.
  • Alkoxy is meant an alkyl group as described above attached via an oxygen bridge.
  • Alkoxy groups include C 1-6 alkoxy and C 1-4 groups, which have from 1 to 6 or from 1 to 4 carbon atoms, respectively.
  • Methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3- hexoxy, and 3-methylpentoxy are representative alkoxy groups.
  • Alkylamino refers to a secondary or tertiary amine that has the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloalkyl and (cycloalkyl)alkyl groups.
  • groups include, for example, mono- and di- (C 1-6 alkyl)amino groups, in which each C 1-6 alkyl may be the same or different.
  • alkyl as used in the term “alkylamino” differs from the definition of "alkyl” used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups.
  • Halogen means fluorine, chlorine, bromine, and iodine.
  • a "haloalkyl” is an alkyl group that is substituted with 1 or more independently chosen halogens (e.g., "C 1-6 haloalkyl” groups have from 1 to 6 carbon atoms and at least one halogen).
  • haloalkyl groups include, but are not limited to, mono-, di- or tri-fluoromethyl; mono-, di- or tri- chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, di-, tri-, tetra- or penta- chloroethyl; and 1,2,2,2-tetrafluoro-l-trifluoromethyl-ethyl.
  • a "heteroaryl” is an aromatic group in which at least one aromatic ring comprises at least one heteroatom selected from N, O and S.
  • Heteroaryls include, for example, 5-12 membered heteroaryls. Examples included but are not limited to imidazole, furan, furazan, isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, tetrazole, thiazole and thiophene.
  • heterocyclic refers to a ring structure containing 3-12 ring atoms, in which at least one ring atom is carbon and at least one ring atom is heteroatom selected from N, O, and S.
  • a heterocyclic group may be aromatic or non-aromatic.
  • Piperidine and oxetane are non-limiting examples of non-aromatic heterocycles.
  • Thiazole and pyridine are non- limiting examples of aromatic heterocycles.
  • a ring substituent may be a moiety such as a halogen, alkyl group, haloalkyl group or other group that is covalently bonded to an atom (preferably a carbon or nitrogen atom) that is a ring member.
  • Substituents of aromatic groups are generally covalently bonded to a ring carbon atom.
  • the term“pharmaceutically acceptable” when used with reference to a compound of formula I is intended to refer to a form of the compound that is safe for administration to a subject.
  • a free base, a salt form, a solvate, a hydrate, a prodrug or derivative form of a compound of formula I which has been approved for mammalian use, via oral ingestion or any other route of administration, by a governing authority or regulatory agency, 26
  • FDA Food and Drug Administration
  • salts Included in the compounds of formula I are the pharmaceutically acceptable salt forms of the free-base compounds.
  • pharmaceutically-acceptable salts embraces salts, commonly used to form alkali metal salts and to form addition salts of free acids or free bases, which have been approved by a regulatory agency. Salts are formed from ionic associations, charge-charge interactions, covalent bonding, complexation, coordination, etc. The nature of the salt is not critical, provided that it is pharmaceutically acceptable.
  • the compound(s) of formula I is used to treat a subject by administering the compound(s) as a pharmaceutical composition.
  • the compound(s) in one embodiment, is combined with one or more pharmaceutically acceptable excipients, including carriers, diluents or adjuvants, to form a suitable composition, which is described in more detail herein.
  • excipient denotes any pharmaceutically acceptable additive, carrier, adjuvant, or other suitable ingredient, other than the active pharmaceutical ingredient (API), which is typically included for formulation and/or administration purposes.
  • API active pharmaceutical ingredient
  • the terms“treat”, “treating,” “treatment,” and “therapy” as used herein refer to therapy, including without limitation, curative therapy, prophylactic therapy, and preventative therapy.
  • Prophylactic treatment generally constitutes either preventing the onset of disorders altogether or delaying the onset of a pre-clinically evident stage of disorders in individuals.
  • the phrase "effective amount" is intended to quantify the amount of each agent, which will achieve the goal of improvement in disorder severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies.
  • the effective amount in one embodiment, is administered in a single dosage form or in multiple dosage forms.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms or by other conventional methods known to those of skill in the art.
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular hedgehog inhibitor employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above. Generally, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.0001 to about 100 mg per kilogram of body weight per day. The mode of administration can have a large effect on dosage. Higher doses may be used for localized routes of delivery.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
  • dose levels can vary as a function of the specific compound, the severity of the symptoms and the susceptibility of the subject to side effects. Dosages for a given compound disclosed herein are readily determinable by those of skill in the art by a variety of means.
  • One embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I, or a stereoisomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.
  • the present invention provides methods for regulating the Wnt signaling pathway and/or treating a Wnt- mediated disorder in a mammal suffering therefrom.
  • the method comprises administrating to a mammalian subject a therapeutically
  • the method comprises treating or preventing disorder is a cell proliferative disorder selected from the group consisting of systemic sclerosis, skin fibrosis, idiopathic pulmonary fibrosis, renal fibrosis, liver fibrosis, drug-induced fibrosis, radiation-induced fibrosis, colorectal cancer, breast cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, non- small cell lung cancer, gastric cancer, pancreatic cancer, leukemia, lymphoma, neuroblastoma, retinoblastoma, sarcoma, osteosarcoma, chondosarcoma, Ewing's sarcoma, rhabdomysarcoma, brain tumor, WiIm' s tumor, basal cell carcinoma, melanoma, head and neck cancer, cervical cancer and prostate cancer.
  • disorder is a cell proliferative disorder selected from the group consisting of systemic sclerosis, skin fibrosis,
  • the compounds described herein are formulated into pharmaceutical compositions.
  • Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inactive ingredients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • a summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed., Easton, Pa.: Mack Publishing Company (1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania (1975); Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y. (1980); and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed., Lippincott Williams & Wilkins (1999), herein incorporated by reference for such disclosure.
  • a pharmaceutical composition refers to a mixture of a compound of formula I with other chemical components (i.e. pharmaceutically acceptable inactive ingredients), such as carriers, excipients, binders, filling agents, suspending agents, flavoring agents, sweetening agents, disintegrating agents, dispersing agents, surfactants, lubricants, colorants, diluents, solubilizers, moistening agents, plasticizers, stabilizers, penetration enhancers, wetting agents, anti-foaming agents, antioxidants, preservatives, or one or more combination thereof.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • therapeutically effective amounts of compounds described herein are administered in a pharmaceutical composition to a mammal having a disease, disorder, or condition to be treated.
  • the mammal is a human.
  • a therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the
  • the compounds can be used singly or in combination with one or more therapeutic agents as components of mixtures.
  • the pharmaceutical formulations described herein are administered to a subject by appropriate administration routes, including but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal administration routes.
  • the pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.
  • dosage units are tablets or capsules.
  • these contain an amount of active ingredient from about 1 to 2000 mg, advantageously from about 1 to 500 mg, and typically from about 5 to 150 mg.
  • a suitable daily dose for a human or other mammal vary widely depending on the condition of the patient and other factors, but, once again, can be determined using routine methods and practices.
  • Conventional formulation techniques include, e.g., one or a combination of methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6) fusion.
  • Other methods include, e.g., spray drying, pan coating, melt granulation, granulation, fluidized bed spray drying or coating (e.g., wurster coating), tangential coating, top spraying, tableting, extruding and the like.
  • Methods of the present invention include the use of at least one compound of formula I, which inhibits hedgehog signaling in the regulation of repair and/or functional performance of a wide range of cells, tissues and organs, and have therapeutic and cosmetic applications ranging from regulation of neural tissues, bone and cartilage formation and repair, regulation of spermatogenesis, regulation of smooth muscle, regulation of lung, liver and other organs arising from the primitive gut, regulation of hematopoietic function, regulation of skin and hair growth, etc. Accordingly, the methods and compositions of the present invention include the use of the subject inhibitors for all such uses as inhibitors of hedgehog proteins may be implicated. Moreover, the subject methods can be performed on cells which are provided in culture (in vitro), or on cells in a whole animal (in vivo). 30
  • the compounds of the present invention can be prepared using various synthetic routes, including those described below, starting from commercially available materials.
  • Starting materials of the invention are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary.
  • the invention further encompasses“intermediate” compounds, including structures produced from the synthetic procedures described, whether isolated or not, prior to obtaining the finally desired compound. Structures resulting from carrying out steps from a transient starting material, structures resulting from divergence from the described method(s) at any stage, and structures forming starting materials under the reaction conditions are all “intermediates” included in the invention. Further, structures produced by using starting materials in the form of a reactive derivative or salt, or produced by a compound obtainable by means of the process according to the invention and structures resulting from processing the compounds of the invention in situ are also within the scope of the invention.
  • New starting materials and/or intermediates, as well as processes for the preparation thereof, are likewise the subject of this invention.
  • such starting materials are used and reaction conditions so selected as to obtain the desired compound(s).
  • Starting materials of the invention are either known, commercially available, or can be synthesized in analogy to or according to methods that are known in the art. Many starting materials may be prepared according to known processes and, in particular, can be prepared using processes described in the examples. In synthesizing starting materials, functional groups in some cases are protected with suitable protecting groups when necessary. Protecting groups, their introduction and removal are described above.
  • Scheme 1 depicts a general synthetic route leading to the synthesis of compounds of Formula I.
  • Compounds of Formula I can be assembled from three components: M1, M2, and M4.
  • Component M1 can be formed from other precursors, as shown in examples vide infra.
  • Component M2 has two leaving groups (LG 1 and LG 2 ) which can undergo reactions with an amino group in component M1 and a chemical group (CG 1 ) in component M4 to form compounds of Formula I.
  • LG 1 and LG 2 can be selected from halide, CH 3 S(O) 2 ⁇ , triflate, tosylate, and mesylate.
  • CG 1 can be selected from borate, organotin, alkyne, amino, and amide groups.
  • Palladium catalyzed reactions of borate, organotin, alkyne, amide, or amino in CG 1 , or treating amino group in CG 1 with a base can form a covalent bond between A and U in M. Further modifications of A or U may be needed to complete the syntheses of compounds of Formula I. Alternatively, LG 2 can be converted to borate and CG 1 can be selected from Br, I, and triflate so that a palladium catalyzed reaction may form the covalent bond between A and U. Further, M1 may only contains shorter tails, such as Q-L- or L- to start with, and Z or Z-Q may be added later to complete the synthesis of compounds of Formula I.
  • Conditions for steps a and d can be: DIPEA, t-BuOH, 50-60 °C, overnight; DIPEA, i-PrOH, 60-80 °C overnight; Et 3 N, THF, rt, overnight; DIPEA, cyclohexanol, ZnCl 2 , 120 °C, 40 h; K 2 CO 3 , 32 DMSO, 120-135 °C, 10 h; Pd(AcO)2, BINAP, t-BuONa, dioxane, 100 °C, 12h; and DIPEA, THF, 50 °C, overnight.
  • Conditions for steps b and c can be: DIPEA, NMP, 120-130°C, overnight; DIPEA, THF, reflux, overnight; DIPEA, t-BuOH, 50 °C; NMP, 130 °C, 24 h; Pd(PPh 3 ) 4 , K 2 CO 3 , dioxane/H 2 O, 100-120 °C, overnight; Cs 2 CO 3 , Pd(PPh 3 ) 4 , dioxane/H 2 O, 100 °C, 12h; Pd(dppf)Cl 2 , dppf, K 3 PO 4 , dioxane, H 2 O, 100 °C, 12 h; Pd(dppf)Cl 2 , dioxane/H 2 O, 100 °C, 10h; and Pd(PPh 3 ) 4 , xantphos, Cs 2 CO 3 , dioxane, reflux, overnight.
  • Scheme 2 illustrates another general synthetic route leading the synthesis of compounds of Formula I.
  • LG 3 can be selected from halide, triflate, tosylate, and mesylate, while CG 2 can be a borate group.
  • LG 3 can be selected from halide, triflate, tosylate, and mesylate; and CG 2 can be a borate group.
  • Palladium catalyzed reaction can lead to the covalent bond formation between A and U in M8.
  • An ensuing reductive amination between M8 and M9 form the covalent bond between L and the amino group on A. Further alkylation of the amino group, if needed, may lead to compounds of Formula I.
  • Step e can be Na 2 CO 3 , Pd(PPh 3 ) 4 , EtOH, toluene, H 2 O, 90 °C, 12h; and K 2 CO 3 , Pd(PPh 3 ) 4 , dioxane/H 2 O, 80 °C, 10-12h.
  • Step f can be 1) EtOH, 90 °C, 12 h, 2) NaBH 4 ; and TFA, Et 3 SiH, MeCN, 80 °C.
  • Scheme 3 depicts a general synthetic route leading to the synthesis of compounds of Formula I.
  • Component M10 can be formed from other precursors, as shown in examples vide infra.
  • the OH group of M13 was converted to hydrogen in two steps to give M14.
  • the CG 3 group of M14 was converted to leaving group (LG 4 ) which can undergo reactions with an amino group in component M1 to form compounds of Formula I.
  • CG 3 can be selected from CH 3 S ⁇ and CH 3 O ⁇ groups.
  • LG 4 can be selected from CH 3 S(O) 2 ⁇ and HO ⁇ groups.
  • Conditions for steps l can be: LDA, THF, -60 °C, 1 h.
  • Conditions for steps m can be: NH 4 OAc, AcOH, 108 °C, 8 h.
  • Conditions for steps n can be: POCl 3 , 100 °C, 1 h.
  • Conditions for steps o can be: Pd(PPh 3 ) 4 , HCOOH, Et 3 N, DMSO, 100 °C, 1-3 h.
  • Conditions for steps p can be: HBr, H 2 O, 100 °C, 1 h; and Oxone, THF, H 2 O, r.t., 10 h.
  • Conditions for steps q can be: PyBOP, DIPEA, DMF, r.t., 12 h; and DIPEA, NMP, 135 °C, 16 h.
  • EXAMPLE 1 Preparation of 5-fluoro-N-(4-(2-methylpyridin-4-yl)benzyl)-6- (naphthalen-2-yl)pyrimidin-4-amine (A-1)
  • Method A-Step a 6-chloro-5-fluoro-N-(4-(2-methylpyridin-4-yl)benzyl)pyrimidin-4- amine
  • Method A-Step b 5-fluoro-N-(4-(2-methylpyridin-4-yl)benzyl)-6-(naphthalen-2- yl)pyrimidin-4- amine 35
  • EXAMPLE 2 Preparation of 5-fluoro-N-methyl-N-(4-(2-methylpyridin-4-yl)benzyl)- 6- (naphthalen-2-yl)pyrimidin-4-amine (A-27)
  • Method A-Step b 6-((5-fluoro-6-(quinolin-6-yl)pyrimidin-4-ylamino)methyl)-2- n
  • EXAMPLE 5 Preparation of 6-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5- fluoro-N-((2- (2-methylpyridin-4-yl)pyrimidin-5-yl)methyl)pyrimidin-4-amine (A-61)
  • Method A-Step a 6-chloro-5-fluoro-N-((2-(2-methylpyridin-4-yl)pyrimidin-5- yl)methyl) pyrimidin-4-amine
  • Method A-Step b 6-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-5-fluoro-N-((2- (2-methylpyridin-4-yl)pyrimidin-5-yl)methyl)pyrimidin-4-amine
  • Method E-Step k 4-(4-((5-fluoro-6-(quinolin-6-yl)pyrimidin-4- ylamino)methyl)
  • Method A-Step a 6-chloro-5-fluoro-N-((3-fluoro-2'-methyl-2,4'-bipyridin-5- yl)methyl)pyrimi
  • Method A-Step b 5-fluoro-N-((3-fluoro-2'-methyl-2,4'-bipyridin-5- yl)methyl)-6-(pyridin-3- ylethynyl)pyrimidin-4-amine
  • EXAMPLE 8 Preparation of 5-fluoro-N-((3-fluoro-2'-methyl-2,4'-bipyridin-5- yl)methyl)-6-(1,7- naphthyridin-6-yl)pyrimidin-4-amine (A-85)
  • Method F-Step l N-(tert-butyl)-3-(2-(5-fluoro-6-methoxypyrimidin-4-yl)-2- oxoethyl) picolinamide
  • EXAMPLE 10 Preparation of 6-(6-(4-(2-methylpyridin-4- yl)benzylamino)pyrimidin-4-yl)-2-(methylthio)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)- one (A-137)
  • Method A-Step b 6-(6-(4-(2-methylpyridin-4-yl)benzylamino)pyrimidin-4- yl)-2-(methylthio) -7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one
  • EXAMPLE 11 Preparation of 2-(methylamino)-6-(6-(4-(2-methylpyridin-4- yl)benzylamino)pyrimidin-4-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one (A-138)
  • EXAMPLE 12 Preparation of N-(4-(2-methylpyridin-4-yl)benzyl)-4- (naphthalen-2-yl)pyridin-2-amine (A-163)
  • EXAMPLE 13 Preparation of 7-((4-(quinolin-6-yl)pyrimidin-2- ylamino)methyl)quinoline-3- carbonitrile (A-179)
  • EXAMPLE 14 Preparation of 2-((3-fluoro-2'-methyl-2,4'-bipyridin-5- yl)methylamino)-4- (1,5-naphthyridin-2-yl)pyridin-3-ol (A-176) [00179] Method A-Step c: 2-(2,3-difluoropyridin-4-yl)-1,5-naphthyridine
  • EXAMPLE 15 Preparation of 5-((4-(1,7-naphthyridin-6-yl)pyrimidin-2- ylamino)methyl)-2'-methyl-2,4'-bipyridine-3-carbonitrile (A-183)
  • Method F-Step l N-tert-butyl-3-(2-(2-(methylthio)pyrimidin-4-yl)-2- oxoethyl)picolinamide
  • EXAMPLE 16 Preparation of 3-((5-(quinolin-6-yl)-1,2,4-thiadiazol-3- ylamino)methyl)quinoline-7-carbonitrile (A-199) [00197] Preparation of 3-(bromomethyl)quinoline-7-carbonitrile
  • EXAMPLE 17 Preparation of N-((3-methoxy-2'-methyl-2,4'-bipyridin-5- yl)methyl)-5-(1,7-naphthyridin-6-yl)-1,2,4-thiadiazol-3-amine (A-196)
  • Method A-Step d N-((3-methoxy-2'-methyl-2,4'-bipyridin-5-yl)methyl)-5- (1,7-naphthyridin-6-yl) -1,2,4-thiadiazol-3-amine
  • Method A-Step c 3-chloro-5-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-1,2,4- thiadiazole
  • Method A-Step d 5-((5-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-1,2,4- thiadiazol-3-ylamino) methyl)-2'-methyl-2,4'-bipyridine-3-carbonitrile
  • EXAMPLE 19 Preparation of 4-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3- fluoro-N-((3-fluoro-2'-methyl '-bipyridin-5-yl)methyl)pyridin-2-amine (A-202)
  • Method A-Step d 4-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-3-fluoro-N-((3- fluoro-2'-meth l-2 4'-bi ridin-5- l meth l ridin-2-amine
  • Table 2 shows a selection of compounds prepared according to the methods discussed above in detail and indicated in the Third column of the table:
  • the primary assay is based on Wnt pathway Super-top flash (STF) reporter gene assay:
  • HEK293 STF stable clones (HEK293 cells stably transfected with "Super-Top Flash" TCF-luciferase reporter plasmid) were kept in complete culture medium (DMEM with 4 mM L-Gln, 1.5 g/L sodium bicarbonate and 4.5 g/L glucose containing 6 ⁇ g/mL Blasticidin and 10% FBS).
  • L Wnt3A cells (CRL-2647, ATCC) were kept in DMEM (Gibico) containing 10% FBS (Hyclone).
  • HEK293 STF and L Wnt3A cells were harvested when 90% confluence and cell suspension was mixed with a fixed ratio of 1:1 (HEK293 STF: L Wnt3A).100 ⁇ L/well of mixed cells suspension was added to the 96-well-plate with final cell concentration of 12,000 cells/well and then cultured for an additional 24 hours before adding compounds.
  • luciferase solution (Bright-Glo, Promega) was added to each well during the 48 h incubation. The plates were incubated at room temperature for 5 min under gentle shaking. Luminescence signaling was measured with a plate reader (PHERAstar FS, BMG). The IC 50 (potency) of compounds was calculated based on the inhibition of luminescence signaling.

Abstract

La présente invention concerne des inhibiteurs de la voie de signalisation Wnt présentant des structures de formule I, conjointement avec leurs sels pharmaceutiques. L'invention concerne également des applications des composés de formule I dans l'inhibition ou la modulation de la voie de signalisation Wnt. Les composés de formule I peuvent traiter des troubles provoqués par une activation aberrante de la voie de signalisation Wnt.
PCT/US2016/055851 2015-10-08 2016-10-06 Inhibiteurs de la voie de signalisation wnt et leurs applications thérapeutiques WO2017062688A1 (fr)

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KR1020187013073A KR20180061363A (ko) 2015-10-08 2016-10-06 Wnt 신호 전달 경로 억제제 및 이의 치료적 적용
EP16854369.2A EP3359154B1 (fr) 2015-10-08 2016-10-06 Inhibiteurs de la voie de signalisation wnt et leurs applications thérapeutiques
JP2018518629A JP6853819B2 (ja) 2015-10-08 2016-10-06 Ｗｎｔシグナル伝達経路阻害剤およびその治療用途
US15/766,799 US10450300B2 (en) 2015-10-08 2016-10-06 Wnt signaling pathway inhibitors and therapeutic applications thereof
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023064585A1 (fr) * 2021-10-14 2023-04-20 Vanderbilt University Dérivés de 7,8-dihydro-5h-1,6-naphtyridine en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4 pour le traitement de troubles neurologiques et psychiatriques

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110189097A1 (en) * 2009-11-09 2011-08-04 Dritan Agalliu Use of WNT inhibitor to inhibit angiogenesis in the CNS
WO2013110433A1 (fr) 2012-01-28 2013-08-01 Merck Patent Gmbh Composés azahétérocycliques
US20140179696A1 (en) * 2012-04-04 2014-06-26 Samumed, Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
WO2014159733A1 (fr) * 2013-03-14 2014-10-02 Curegenix, Inc. Composés pour le traitement de maladies de fibrose
WO2014165232A1 (fr) * 2013-03-12 2014-10-09 Curegenix, Inc. Composés pour le traitement du cancer

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110189097A1 (en) * 2009-11-09 2011-08-04 Dritan Agalliu Use of WNT inhibitor to inhibit angiogenesis in the CNS
WO2013110433A1 (fr) 2012-01-28 2013-08-01 Merck Patent Gmbh Composés azahétérocycliques
US20140179696A1 (en) * 2012-04-04 2014-06-26 Samumed, Llc Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof
WO2014165232A1 (fr) * 2013-03-12 2014-10-09 Curegenix, Inc. Composés pour le traitement du cancer
WO2014159733A1 (fr) * 2013-03-14 2014-10-02 Curegenix, Inc. Composés pour le traitement de maladies de fibrose

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"Pharmaceutical Dosage Forms and Drug Delivery Systems", 1999, LIPPINCOTT WILLIAMS & WILKINS
"Pharmaceutical Dosage Forms", 1980, MARCEL DECKER
"Remington: The Science and Practice of Pharmacy", 1995, MACK PUBLISHING COMPANY
BOUTROSMLODZIK, MECH. DEV., vol. 83, 1999, pages 27 - 37
CHENNWALSH, SCIENCE, vol. 297, 2002, pages 365 - 9
DAHMEN ET AL., CANCER RES., vol. 61, 2001, pages 7039 - 43
HOANG ET AL., INT. J. CANCER, vol. 109, 2004, pages 106 - 111
HOOVERJOHN E.: "Remington's Pharmaceutical Sciences", 1975, MACK PUBLISHING CO.
J.F.W. MCOMIE: "Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
KLAUSBIRCHMEIER, NAT. REV. CANCER, vol. 8, 2008, pages 387 - 98
LOGANNUSSE, ANNU. REV. CELL DEV. BIOL., vol. 20, 2004, pages 781 - 810
PERRIMON, CELL, vol. 76, 1994, pages 781 - 4
REYACLEVERS, NATURE, vol. 434, 2005, pages 843 - 850
T.W. GREENE: "Protective Groups in Organic Synthesis", vol. 3, 1981, ACADEMIC PRESS

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023064585A1 (fr) * 2021-10-14 2023-04-20 Vanderbilt University Dérivés de 7,8-dihydro-5h-1,6-naphtyridine en tant que modulateurs allostériques positifs du récepteur muscarinique de l'acétylcholine m4 pour le traitement de troubles neurologiques et psychiatriques

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