WO2022199627A1 - Polycyclic compounds and uses thereof - Google Patents
Polycyclic compounds and uses thereof Download PDFInfo
- Publication number
- WO2022199627A1 WO2022199627A1 PCT/CN2022/082548 CN2022082548W WO2022199627A1 WO 2022199627 A1 WO2022199627 A1 WO 2022199627A1 CN 2022082548 W CN2022082548 W CN 2022082548W WO 2022199627 A1 WO2022199627 A1 WO 2022199627A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- optionally substituted
- group
- hydrogen
- independently selected
- heteroaryl
- Prior art date
Links
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- 101001098818 Homo sapiens cGMP-inhibited 3',5'-cyclic phosphodiesterase A Proteins 0.000 claims abstract 14
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- 101000864272 Homo sapiens Schlafen family member 12 Proteins 0.000 claims abstract 12
- 102100029916 Schlafen family member 12 Human genes 0.000 claims abstract 12
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- DRDVJQOGFWAVLH-UHFFFAOYSA-N tert-butyl n-hydroxycarbamate Chemical compound CC(C)(C)OC(=O)NO DRDVJQOGFWAVLH-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 229950004127 trequinsin Drugs 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001195 ultra high performance liquid chromatography Methods 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000012447 xenograft mouse model Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention belongs to the chemical field, and in particularly relates to the Anagrelide and its derivatives and the uses thereof in the preparation of pharmaceuticals or pharmaceutical compositions for the treatment of inhibition of tumors.
- Cancers continue to be a major global public health problem and is one of the leading causes of death globally, and is responsible for an estimated 10 million deaths annually (WHO) .
- WHO World Health Organization
- anti-tumor agents including small molecules, and immunomodulatory agents
- Current treatments do not provide an ideal cure; drug resistance, low efficacy, and tolerability issues majorly limited the efficacy of these treatments.
- novel therapeutic agents that treat, ameliorate or cure cancer.
- E2 human 17- ⁇ -estradiol
- PDE3A phosphodiesterase 3A
- SLFN12 an otherwise fast-turnover protein Schlafen 12
- Bcl-2 and Mcl-1 phosphodiesterase 3A
- Polycyclic agents such as Anagrelide (Agrylin/Xagrid)
- Anagrelide is a phosphodiesterase inhibitor useful affecting blood cell functions such as proliferation, maturation, and differentiation. It is a drug used for the treatment of essential thrombocytosis (also known as essential thrombocythemia) , or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia. However, functions and mechanisms of these polycyclic compounds in the treatment of tumor have not been well-understood.
- the present invention relates to novel antitumor compounds, pharmaceutical compositions comprising such compounds, as well as methods of modulating the PDE3A activity or regulating the interaction of PDE3A/SLFN12, thus has potential to be developed as effective antitumor agents.
- the objective of the invention is to provide a compound, a composition, and a method for modulating the PDE3A activity or regulating the interaction of PDE3A/SLFN12.
- Compounds of the present invention modulate the PDE3A activity or regulate the interaction of PDE3A/SLFN12, and are useful as antitumor agents.
- the present invention includes methods for preparing the compounds of the invention.
- the present invention provides a compound of Formula (I) or Formula (I’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl, ; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
- B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S, optionally substituted C 1 -C 10 alkylamino, optionally substituted C 6 -C 10 arylamino, optionally substituted C 3 -C 10 cycloalkylamino, optionally substituted-C 1 -C 10 alkyl or heteroalkyl, optionally substituted-C 2 -C 8 alkenyl or heteroalkenyl, optionally substituted-C 2 -C 8 alkynyl or heteroalkynyl and optionally-C 1 -C 10 substituted alkoxyl or heteroalkoxyl;
- group G is selected from CR 7 R 8 -, -C (O) -, -O-, -NR 9 -, -S-and-S (O) 2 -;
- R 7 , R 8 and R 9 are independently selected from hydrogen, halogen, CN, optionally substituted-C 2 -C 8 alkyl or heteroalkyl, optionally substituted-C 2 -C 8 alkenyl or heteroalkenyl, optionally substituted-C 2 -C 8 alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted -C 3 -C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
- group K is selected from CR 10 R 11 -, -C (O) -, -O-, -NR 12 -, -S-and-S (O) 2 -; n is 0, 1, 2, 3 or 4; R 10 , R 11 and R 12 are independently selected from hydrogen, halogen, CN, optionally substituted -C 2 -C 8 alkyl or heteroalkyl, optionally substituted-C 2 -C 8 alkenyl or heteroalkenyl, optionally substituted-C 2 -C 8 alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted-C 3 -C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
- the compound of Formula (I) or Formula (I’) is not a compound selected from the following compounds:
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted (C1-C10) alkyl or (C1-C10) heteroalkyl, optionally substituted (C1-C10) aryl or (C1-C10) heteroaryl, optionally substituted (C2-C4) alkenyl or (C6-C8) alkenyl, optionally substituted (C2-C4) alkynyl or (C6-C8) alkynyl, (C1-C6) alkoxyl or (C6-C8) alkoxyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl-SO 2
- R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen, deuterium, halogen, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy, optionally substituted hydroxy, amino, optionally substituted amino, optionally substituted (C1-C6) alkyl, (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl, (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl -SO 2 -, (C3-C6) cycloalkyl, or a (C5-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O,
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently hydrogen, deuterium, halogen, hydroxyl or optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl, or (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently hydrogen, deuterium, halogen, hydroxy, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, Si and S.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are all hydrogen.
- ring A is hydrophobic.
- ring A is selected from optionally substituted 3-to 6-membered heterocycle and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S. In some embodiments, ring A is selected from optionally substituted 3-to 6-membered aryl or heteroaryl; wherein the heteroatom is selected from the group consisting of N, O and S.
- ring A is selected from optionally substituted-C 5 -C 6 cycloalkyl or heterocycle and optionally substituted 5-to 6-membered aryl or heteroaryl; wherein the heteroatom is selected from the group consisting of N, O and S.
- ring A is optionally substituted aryl or heteroaryl group derived from one of the following by removal of one hydrogen atom:
- S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
- ring A is optionally substituted 6-membered aryl or heteroaryl group derived from one of the following by removal of one hydrogen atom:
- S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
- ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, Cl, Br, F, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si and S.
- the optionally substituted groups are the same or different substituents and independently selected from hydrogen
- ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, Cl, Br, F, CN, methyl, ethyl, vinyl and ethynyl.
- G is selected from CR 7 R 8 -, -C (O) -, -O-, -NR 9 -, -S-and-S (O) 2 -;
- R 7 and R 8 are same or different;
- R 7 , R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2 -C 8 alkyl or heteroalkyl, optionally substituted-C 2 -C 8 alkenyl or heteroalkenyl, optionally substituted -C 3 -C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted 3-and 8-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
- R 7 and R 8 are same or different;
- R 7 , R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, CN, optionally substituted-C 2 -C 6 alkyl or heteroalkyl, optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted-C 3 -C 6 aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
- G is CR 7 R 8 -;
- R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2 -C 6 alkyl or heteroalkyl, or optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P and S.
- G is CR 7 R 8 -;
- R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S.
- G is CR 7 R 8 -; R 7 and R 8 are different and independently selected from hydrogen, deuterium and halogen.
- K is selected from CR 10 R 11 -, -C (O) -, -O-, -NR 12 -, -S-and-S (O) 2 -; n is 0, 1, 2, 3 or 4; R 10 and R 11 are same or different; R 10 , R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2 -C 8 alkyl or heteroalkyl, optionally substituted-C 2 -C 8 alkenyl or heteroalkenyl, optionally substituted-C 3 -C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted 3-and 8-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
- K is CR 10 R 11 -; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from hydrogen, deuterium, halogen, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S.
- K is CR 10 R 11 -; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from hydrogen, deuterium, halogen and optionally substituted phenyl. In some embodiments, K is CR 10 R 11 -; n is 1, 2 or 3; R 10 and R 11 are same or different, and independently selected from hydrogen, deuterium and halogen. In some embodiments, K is CR 10 R 11 -; n is 1, 2 or 3; R 10 and R 11 are different and independently selected from hydrogen, deuterium and halogen.
- B is selected from optionally substituted-C 1 -C 6 alkyl or heteroalkyl, optionally substituted-C 2 -C 6 alkenyl or heteroalkenyl, optionally substituted-C 2 -C 6 alkynyl or heteroalkynyl and optionally-C 1 -C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is selected from optionally substituted-C 1 -C 2 alkyl or heteroalkyl, optionally substituted–C 2 -C 3 alkenyl or heteroalkenyl, optionally substituted–C 2 -C 3 alkynyl or heteroalkynyl and optionally-C 1 -C 2 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is selected from optionally substituted–C 3 -C 4 alkyl or heteroalkyl, optionally substituted–C 5 -C 6 alkyl or heteroalkyl, optionally substituted–C 4 -C 6 alkenyl or heteroalkenyl, optionally substituted–C 4 -C 6 alkynyl or heteroalkynyl, optionally –C 3 -C 4 substituted alkoxyl or heteroalkoxyl and optionally–C 5 -C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- the optional substitutes are same or different and independently selected from heteroatom
- B is optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S; preferably, the optional substitutes are same or different and independently selected from optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is F
- G is CR 7 R 8 -, wherein R 7 and R 8 are different and independently selected from hydrogen and halogen (F, Cl or Br)
- K is CR 10 R 11 -, wherein R 9 and R 10 are same or different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3.
- B is Cl
- G is CR 7 R 8 -, wherein R 7 and R 8 are different and independently selected from hydrogen and halogen (F, Cl or Br)
- K is CR 10 R 11 -, wherein R 9 and R 10 are different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3.
- B is Br
- G is CR 7 R 8 -, wherein R 7 and R 8 are different and independently selected from hydrogen and halogen (F, Cl or Br)
- K is CR 10 R 11 -, wherein R 9 and R 10 are same or different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3.
- n 1
- n 2 and K represent the same group or different groups.
- R 3 , R 4 , R 5 and R 6 are independently defined as above.
- R 3 , R 4 , R 5 , and R 6 are independently defined as above.
- R 3 , R 4 , R 5 , and R 6 are independently defined as above.
- R 5 , and R 6 are independently defined as above.
- X, Y, Z, W and Q are combined with other atoms to form optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
- R 3 , and R 4 are independently defined as above.
- the present invention provides a compound of Formula (II) or Formula (II’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , ring A, B, X, Y, Z, W and Q are the same as previously defined in the formula (I) or formula (I’) ;
- R a , R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN,hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; and
- the compound of Formula (II) or Formula (II’) is not a compound selected from the following compounds:
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b and R c are independently selected from hydrogen, deuterium, F, Cl, Br, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S; and/or R a , R b , and R c are independently selected from hydrogen, deuterium, F, Cl, Br, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
- R a , R b , and R c are independently selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- R a is halogen (F, Cl or Br)
- R b is selected from hydrogen, deuterium and halogen (F, Cl or Br)
- R c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- ring A is hydrophobic.
- ring A is selected from optionally substituted-C 3 -C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si, Se and S.
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si and S.
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 6-membered heterocycle, optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S.
- ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S.
- ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein 6-membered aryl or heteroaryl are derived from one of the following by removal of one hydrogen atom:
- S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
- ring A is optionally substituted phenyl, wherein the phenyl is derived from the following by removal of one hydrogen atom:
- S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si and S.
- ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, Cl, Br, F, CN, methyl, ethyl, vinyl and ethynyl.
- B is selected from optionally substituted-C 1 -C 6 alkyl or heteroalkyl, optionally substituted-C 2 -C 6 alkenyl or heteroalkenyl, optionally substituted-C 2 -C 6 alkynyl or heteroalkynyl and optionally-C 1 -C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is selected from optionally substituted-C 1 -C 2 alkyl or heteroalkyl, optionally substituted–C 2 -C 3 alkenyl or heteroalkenyl, optionally substituted–C 2 -C 3 alkynyl or heteroalkynyl and optionally-C 1 -C 2 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is selected from optionally substituted–C 3 -C 4 alkyl or heteroalkyl, optionally substituted–C 5 -C 6 alkyl or heteroalkyl, optionally substituted–C 4 -C 6 alkenyl or heteroalkenyl, optionally substituted–C 4 -C 6 alkynyl or heteroalkynyl, optionally –C 3 -C 4 substituted alkoxyl or heteroalkoxyl and optionally–C 5 -C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- the optional substitutes are same or different and independently selected from heteroatom
- B is optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S; preferably, the optional substitutes are same or different and independently selected from optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is F; R a is halogen (F, Cl or Br) ; R b is selected from hydrogen, deuterium and halogen (F, Cl or Br) ; R c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- B is Cl; R a is halogen (F, Cl or Br) ; R b is selected from deuterium and halogen (F, Cl or Br) ; R c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- R 3 , R 4 , R 5 , and R 6 are independently defined as above.
- R 3 , R 4 , R 5 , and R 6 are independently defined as above.
- R 3 , R 4 , R 5 , and R 6 are independently defined as above.
- R 5 , and R 6 are independently defined as above.
- X, Y, Z, W and Q are combined with other atoms to form optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
- R 3 , and R 4 are independently defined as above.
- the present invention provides a compound of Formula (III) or Formula (III’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , ring A and B are the same as previously defined in the formula (I) , formula (I’) , formula (II) or formula (II’) ;
- R a , R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; and
- the compound of Formula (III) or Formula (III’) is not a compound selected from the following compounds:
- R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R a , R b and R c are independently selected from hydrogen, deuterium, F, Cl, Br, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
- R 1 , R 2 , R 3 , R 4 , R 5 , R a , R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
- R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S; and/or R a , R b , and R c are independently selected from hydrogen, deuterium, F, Cl, Br, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
- R a , R b , and R c are independently selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- R a is halogen (F, Cl or Br)
- R b is selected from hydrogen, deuterium and halogen (F, Cl or Br)
- R c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- ring A is hydrophobic.
- ring A is selected from optionally substituted-C 3 -C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si, Se and S.
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si and S.
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, and S.
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 6-membered heterocycle, optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S. In some embodiments, ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S.
- ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein 6-membered aryl or heteroaryl are derived from one of the following by removal of one hydrogen atom:
- S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
- ring A is optionally substituted phenyl, wherein the phenyl is derived from the following by removal of one hydrogen atom:
- S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si and S.
- ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, Cl, Br, F, CN, methyl, ethyl, vinyl and ethynyl.
- substituted phenyl is a phenyl substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 alkyl-amino, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C10 alkenyl, C2-C10 alkenyloxy, C2-C10 alkynyl, C2-C10 alkynyloxy, C1-C10 carboxyl and C1-C10 ester group.
- substituted phenyl is a phenyl substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkenyloxy, C2-C6 alkynyl, C2-C6 alkynyloxy, C1-C6 carboxyl and C1-C6 ester group.
- substituted means that one or more hydrogens in the described objective (a group or a ring) can be substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen (such as F, Cl, Br, I) , nitro (-NO 2 ) , amino (NH 2 ) , C1-C10 alkyl (such as methyl, ethyl, isopropyl, n-propyl, butyl) , C1-C10 alkoxy (such as methoxy, ethoxy, isopropoxy, n-propoxy, butoxy) , C1-C10 haloalkyl (such as CHF 2 , CF 3, CH 2 CHF 3 ) , C1-C10 haloalkoxy, C1-C10 alkyl-amino (such as methylamino, ethylamino, propylamino, butylamino
- substituents selected from the group consisting of hydroxy
- the one or more substituents are selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C2-C6 alkynyl, C2-C6 alkoxy, C1-C6 carboxyl and C1-C6 ester group.
- the one or more substituents are selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkenyloxy, C2-C6 alkynyl, C2-C6 alkynyloxy, C1-C6 carboxyl and C1-C6 ester group.
- B is selected from optionally substituted-C 1 -C 6 alkyl or heteroalkyl, optionally substituted-C 2 -C 6 alkenyl or heteroalkenyl, optionally substituted-C 2 -C 6 alkynyl or heteroalkynyl and optionally-C 1 -C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- substituted amino is an amino substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 alkyl-amino, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C10 alkenyl, C2-C10 alkenyloxy, C2-C10 alkynyl, C6-C10 aryl, C6-C10 aryl-amino, C2-C10 alkynyloxy, C1-C10 carboxyl and C1-C10 ester group.
- substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloal
- substituted amino is an amino substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkenyloxy, C2-C6 alkynyl, C2-C6 alkynyloxy, C1-C6 carboxyl and C1-C6 ester group.
- B is selected from optionally substituted-C 1 -C 2 alkyl or heteroalkyl, optionally substituted–C 2 -C 3 alkenyl or heteroalkenyl, optionally substituted–C 2 -C 3 alkynyl or heteroalkynyl and optionally-C 1 -C 2 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is selected from optionally substituted–C 3 -C 4 alkyl or heteroalkyl, optionally substituted–C 5 -C 6 alkyl or heteroalkyl, optionally substituted–C 4 -C 6 alkenyl or heteroalkenyl, optionally substituted–C 4 -C 6 alkynyl or heteroalkynyl, optionally –C 3 -C 4 substituted alkoxyl or heteroalkoxyl and optionally–C 5 -C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- the optional substitutes are same or different and independently selected from heteroatom
- B is optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S; preferably, the optional substitutes are same or different and independently selected from optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
- B is F; R a is halogen (F, Cl or Br) ; R b is selected from hydrogen, deuterium and halogen (F, Cl or Br) ; R c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- B is Cl; R a is halogen (F, Cl or Br) ; R b is selected from deuterium and halogen (F, Cl or Br) ; R c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
- the present invention provides a compound of Formula (IV) or Formula (IV’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
- R 1 , R 2 , R 3 , R 4 , and R 5 , ring A and B are the same as previously defined in the formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) .
- R a , R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
- R 1 , R 2 , R 3 , R 4 , and R 5 are hydrogen.
- R a is chloro.
- R c is hydrogen.
- R a is chloro.
- R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, deuterium, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 10 heteroaryl;
- R a is chloro,
- R b and R c are independently hydrogen, deuterium, C 1 -C 6 alkyl, C 6 -C 10 aryl, or C 3 -C 10 heteroaryl.
- R b is hydrogen, chlorine, bromine, or fluorine
- R 1 , R 2 , R 3 , R 4 , and R 5 are independently hydrogen, deuterium, C 1 -C 6 alkyl, C 6 -C 10 aryl, C 3 -C 10 heteroaryl
- R a is chloro
- R b and R c are independently hydrogen, deuterium, C 1 -C 6 alkyl, C 6 -C 10 aryl, or C 3 -C 10 heteroaryl
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle and optionally substituted 3-to 6-membered aryl or heteroaryl
- hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, and S
- B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, and S, optionally substituted-C 1 -C 10 alky
- ring A is selected from optionally substituted-C 3 -C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, and S.
- B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, and S, optionally substituted C 1 -C 10 alkylamino, optionally substituted C 6 -C 10 arylamino, optionally substituted C 3 -C 10 cycloalkylamino, optionally substituted-C 1 -C 10 alkyl or heteroalkyl, optionally substituted-C 2 -C 8 alkenyl or heteroalkenyl, optionally substituted-C 2 -C 8 alkynyl or heteroalkynyl and optionally-C 1 -C 10 substituted alkoxyl or heteroalkoxyl.
- the compound of Formula (IV) or Formula (IV’) is not a compound selected from the following compounds:
- the compounds are selected from the group consisting of the followings:
- the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
- the compounds of the present invention may contain one or more isotopic forms, either hydrogen isotopic forms of D or T, or isotopic isoform of any atoms, such as C, N, P, or S. All isotopic forms are contemplated to be within the scope of the present invention.
- the polycyclic compounds of the present invention act as molecular glue to form a stable ternary complex with PDE3A and SLFN12, and interact more favorably with the interfacial residues of SLFN12. It was found that the polycyclic compounds of the present invention were engaged in the hydrophobic interaction with Thr844, Phe972, Leu910 in PDE3A and Ile557, Ile558 in SLFN12 in a structure-effect analysis. This is a critical interaction. It is further found that these compounds are significantly stronger compared with the Anagrelide analogue. Especially, compounds with ring A, especially the hydrophobic ring A, perform much better than those with hydrophilic group at the same position.
- the present invention provides a pharmaceutical composition containing the compound of the formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) , formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts and/or prodrug thereof, and also containing at least one pharmaceutically acceptable diluents, excipients or carriers.
- the pharmaceutical composition is in a form suitable for oral, topical, transdermal, injection, rectal or inhalation administration, especially in the form of tablets, capsules, solutions, liquids, gels, ointments, syrup, spray, nebulizer or suppositories.
- the present invention provides compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for use as PDE3A modulator and/or SLFN12 modulator.
- the modulator is capable of inhibiting, disrupting and/or accelerating the activity of PDE3A and/or the activity of SLFN12.
- the present invention provides compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for use as chemicals regulating PDE3A and SLFN12 interaction.
- the chemical is capable of enhancing and/or promoting the interaction of PDE3A and SLFN12.
- the present invention provides use of compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for the manufacture of a medicament to treat or prevent a disease or disorder associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12.
- the present invention provides use of compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for the treatment or prevention of a disease or disorder associated with cancer or tumor, preferably for treatment or inhibition of tumor and/or inhibition of growth of tumor cells.
- the cancer or tumor is selected from Leukemia, lymphoma, myelodysplastic syndrome or myeloma, preferably selected from acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute T-cell leukemia, acute lymphoblastic leukaemia (all) , chronic lymphoblastic leukemia (CLL) , acute monocytic leukemia (amol) , mantle cell lymphoma (MCL) , B-cell lymphoma Histiocytic lymphoma or multiple myeloma.
- AML acute myeloid leukemia
- CML chronic myeloid leukemia
- T-cell leukemia acute lymphoblastic leukaemia
- ALL acute lymphoblastic leukaemia
- CLL chronic lymphoblastic leukemia
- amol acute monocytic leukemia
- MCL mantle cell lymphoma
- the cancer or tumor is selected from: adenocarcinoma, squamous cell carcinoma, adenosarcoma, undifferentiated carcinoma, large cell carcinoma or small cell carcinoma, hepatocellular carcinoma, hepatoblastoma, colon adenocarcinoma, renal cell carcinoma, renal cell adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, glioblastoma, glioma, head and neck cancer, lung cancer, breast cancer, Merkel cell carcinoma, rhabdomyosarcoma, malignant melanoma, Epidermoid carcinoma, lung cancer, renal cancer, adenocarcinoma of the breast, breast cancer, breast cancer, non-small cell lung cancer, ovarian cancer, oral cancer, anal cancer, skin cancer, Ewing's sarcoma, gastric cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer,
- the cancer is associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12.
- the present invention provides a method for preventing or treating a disease or disorder associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12, comprising administering to a subject in need thereof compounds of formula (I) , formula (II) , formula (III) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof or the pharmaceutical composition according to the present invention.
- the present invention provides a method for preventing or treating a disease or disorder of cancer or tumor, comprising administering to a subject in need thereof compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition according to the present invention.
- the present invention features improved methods of identifying patients having cancer (e.g., melanoma, endometrium, lung, hematopoetic/lymphoid, ovarian, cervical, soft tissue sarcoma, leiomyosarcoma, urinary tract, pancreas, thyroid, kidney, glioblastoma and/or breast cancer) that is sensitive to treatment with the compounds in the present invention in modulating the function of PDE3A or the interaction of PDE3A/SLFN12 in a cancer cell derived from such patients.
- cancer e.g., melanoma, endometrium, lung, hematopoetic/lymphoid, ovarian, cervical, soft tissue sarcoma, leiomyosarcoma, urinary tract, pancreas, thyroid, kidney, glioblastoma and/or breast cancer
- the compounds described herein are suitable for monotherapy and are effective against cancer.
- the compounds described herein are suitable for use in combination therapy.
- the additional therapeutic agent could be selected from immune modulator or immune stimulator therapies, which includes but not limited to PD-1, PD-L1 or other CAR-T therapies.
- the compound and the additional therapeutic agent could be co-administered or administered separately.
- administering the compound of the invention allows for administering of the additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating cancer in an individual in need thereof.
- FIG. 1 Compound A0 induced cell death in HeLa cells dependents on PDE3A and SLFN12.
- HeLa, HeLa (PDE3A -/- ) and HeLa (SLFN12 -/- ) cells were treated with A0 at the indicated concentration for 48 h.
- Cell viability was determined by measuring ATP levels. Data are represented as mean ⁇ SD of triplicate wells.
- FIG. 1 Compound A6 induced cell death in HeLa cells dependents on PDE3A and SLFN12.
- HeLa, HeLa (PDE3A -/- ) and HeLa (SLFN12 -/- ) cells were treated with A6 at the indicated concentration for 48 h.
- Cell viability was determined by measuring ATP levels. Data are represented as mean ⁇ SD of triplicate wells.
- Compound A6 shows tumor growth inhibitory effect.
- a Female BALB/c-Nude mice subcutaneously inoculated with HeLa cells. After 7 days, the mice were treated with Vehicle, Anagrelide (5 mg/kg) , A6 (5 mg/kg) , or A6 (1 mg/kg) by oral gavage. Shown are representative photos of mice on day 21.
- b Typical photos of tumors from the Vehicle, Anagrelide (5 mg/kg) , A6(5 mg/kg) , or A6 (1 mg/kg) treated mice. Mice were sacrifificed after treatment for 21 days; tumors were dissected and photographed.
- c The tumor growth curves of the tumor-burdened mice.
- Student’s t-test (two-tailed, unpaired) was performed, ns not signifificant, *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 for comparisons of A6 (5 mg/kg) -, anagrelide (5 mg/kg) -, or A6 (1 mg/kg) -treated group with untreated group (vehicle) .
- d Body weight curves of the tumor-burdened mice. The average body weight ⁇ SD for each cohort is displayed (n 5/group) .
- pharmaceutically acceptable salt or prodrug of a compound means a salt that is pharmaceutically acceptable and that it possesses the desired pharmacological activity of the parent compound.
- subject and “patient” are used herein interchangeably and refer to mammals, in particular humans.
- aryl refers to a mono-or polycyclic carboring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
- a polycyclic aryl is a polyring system that comprises at least one aromatic ring.
- Polycyclic aryls can comprise fused ring, covalently attached ring or a combination thereof.
- heteroaryl refers to a mono-or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
- Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
- a polycyclic heteroaryl can comprise fused ring, covalently attached ring or a combination thereof.
- aromatic groups can be substituted or unsubstituted.
- cyclic aryl or “cyclic heteroaryl” refers to a ring system consisting of two ring wherein at least one ring is aromatic; and the two ring can be fused or covalently attached.
- alkyl refers to saturated, straight-or branched-chain hydrocarbyl radicals.
- "Ci-Cs alkyl, ” “Ci-Ce alkyl, ” “Ci-Cio alkyl” “C2-C4 alkyl, ” or “C3-C alkyl, ” refer to alkyl groups containing from one to three, one to six, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively.
- Ci-Ce alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, ⁇ -butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
- alkenyl refers to straight-or branched-chain hydrocarbyl radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
- C2-C10 alkenyl, ” “C2-C8 alkenyl, ” “C2-C4 alkenyl, ” or “C3-C6 alkenyl, ” refer to alkenyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively.
- Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.
- alkynyl refers to straight-or branched-chain hydrocarbyl radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom.
- C2-C10 alkynyl, ” “C2-C8 alkynyl, ” “C2-C4 alkynyl, ” or “C3-C6 alkynyl, ” refer to alkynyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively.
- Representative alkynyl groups include, but are not limited to, ethynyl, l-propynyl, l-butynyl, heptynyl, octynyl, and the like.
- cycloalkyl refers to a monocyclic or polycyclic saturated carboring or a bi-or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefmic, iminic or oximic double bond.
- Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl.
- C3-C12 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo [2.2. l] heptyl, bicyclo [3. l. 0] hexyl, spiro [2.5] octyl, 3-methylenebicyclo [3.2. l] octyl, spiro [4.4] nonanyl, and the like.
- cycloalkenyl refers to monocyclic or polycyclic carboring or a bi-or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocycbc olefmic, iminic or oximic double bond.
- Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups.
- C3-C12 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2. l] hept-2-enyl, bicyclo [3. l. 0] hex-2-enyl, spiro [2.5] oct-4-enyl, spiro [4.4] non-lenyl, bicyclo [4.2. l] non-3-en-9-yl, and the like.
- arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CEhCEh-phenyl.
- substituted refers to one or more hydrogen atoms in the group are Substituted by one or more substituents selected from the group consisting of C1-C10 alkyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy, halogengen, hydroxy, carboxyl, C1-C10 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, and phenyl group;
- substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
- alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, l-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
- Preferred alkoxy are (C1-C3) alkoxy. It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
- heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi-or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quatemized, (v) any of the above ring may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxosubstituted or optionally substituted with exocyclic olefmic, iminic or oximic double bond.
- heterocycloalkyl groups include, but are not limited to, l, 3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo [2.2. l] -heptyl, 8-azabicyclo [3.2.
- heterocyclic groups may be further substituted.
- Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible) .
- any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom (s) .
- One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
- substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, deuterium, tritium, -F, -Cl, -Br, -I, -OH, Alkyls, aryls
- halogen or “halogengen” alone or as part of another substituents, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
- optionally substituted means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group (s) individually and independently selected from groups described herein.
- hydroxogen includes hydrogen and deuterium.
- the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
- the compounds of each formula herein are defined toinclude isotopically labelled compounds.
- An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope.
- one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20%or at least 50%.
- Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analog, and therefore exhibit a longer half-life when administered to a subject.
- Such compounds can synthesize using methods known in the art, for example by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable.
- hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the hydroxy protecting group as described herein may be selectively removed.
- protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
- amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the amino protecting group as described herein may be selectively removed.
- protected amino refers to an amino group protected with an amino protecting group as defined above.
- subject refers to an animal.
- the animal is a mammal. More preferably, the mammal is a human.
- a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, and the like.
- the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
- modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system) , increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
- the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -, or as (D) -or (L) -for amino acids.
- the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
- Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
- any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbonheteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
- the term "pharmaceutically acceptable salt, " refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
- Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, etal. Describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) .
- the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
- nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
- salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pam
- Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
- Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
- pharmaceutically acceptable ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
- Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
- esters include but are not limited to, esters of Ci-C6-alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.
- compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
- diluents refers to diluents, excipients or carriers that are suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio.
- “Diluents” are agents which are added to the bulk volume of the active agent making up the solid composition.
- Excipients can be binders, lubricants, glidants, coating additives or combinations thereof.
- Carriers can be solvents, suspending agents or vehicles, for delivering the instant compounds to a subject.
- materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
- the carriers comprise one or more of phosal 50 propylene glycol (PG) , polyethylene glycol (PEG) 400, PEG300, DMSO, ehanol, and Tween 80.
- the compound of the present invention is formulated for oral dosing in phosal 50 propylene glycol (PG) , polyethylene glycol (PEG) 400 and ethanol. According to some embodiments, the compound of the present invention is formulated for oral dosing in 40-65%phosal 50 propylene glycol (PG) , 10-40%polyethylene glycol (PEG) 400 and 5-15%ethanol. According to some embodiments, the compound of the present invention is formulated for oral dosing in 50-65%phosal 50 propylene glycol (PG) , 20-30%polyethylene glycol (PEG) 400 and 5-15%ethanol.
- the compound of the present invention is formulated for oral dosing in phosal 50 propylene glycol (PG) , polyethylene glycol (PEG) 400 and DMSO. According to some embodiments, the compound of the present invention is formulated for oral dosing in 40-65%phosal 50 propylene glycol (PG) , 30-40%polyethylene glycol (PEG) 400 and 2-5%DMSO.
- the compound of the present invention is formulated for example for oral dosing in formulation: DMSO, PEG300, and Tween80. According to some embodiments, the compound of the present invention is formulated in formulation: 2-5%DMSO, 30%PEG300, 2-5%Tween80.
- compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
- the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
- Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l, 3-butanediol.
- a nontoxic parenterally acceptable diluent or solvent for example, as a solution in l, 3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil can be employed including synthetic mono-or diglycerides.
- fatty acids such as oleic acid are used in the preparation of injectable.
- the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the rate of drug release can be controlled.
- biodegradable polymers include poly (orthoesters) and poly (anhydrides) .
- Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
- compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
- compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
- the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
- embedding compositions that can be used include polymeric substances and waxes.
- Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
- the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
- Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
- Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
- Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
- dosage forms can be made by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin.
- the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
- Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs.
- Delivery of aerosolized therapeutics, particularly aerosolized antibiotics is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al, U.S. Pat. No. 5,508,269 to Smith et al, and WO 98/43650 by Montgomery, all of which are incorporated herein by reference) .
- An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
- viral infections, conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
- a therapeutically effective amount of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
- the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect) .
- An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
- the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
- the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
- Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
- treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound (s) of this invention per day in single or multiple doses.
- the compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
- the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
- the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
- the amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
- a typical preparation will contain from about 5%to about 95%active compound (w/w) .
- such preparations may contain from about 20%to about 80%active compound. Lower or higher doses than those recited above may be required.
- Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.
- a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
- the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
- compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents
- both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95%of the dosage normally administered in a monotherapy regimen.
- the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
- additional therapeutic or prophylactic agents includes but not limited to, immune therapies (eg.
- compositions according to the invention may also be used in combination with gene replacement therapy.
- Cell survival assay was performed using Cell Titer-Glo Luminescent Cell Viability Assay kit.
- a Cell Titer-Glo assay (Promega) was performed according to the manufacturer’s instructions. Luminescence was recorded with a Tecan GENios Pro plate reader.
- HeLa (SLFN12 -/- ) -3 ⁇ Flag-HA-SLFN12 (wild type (WT) or K213R) cells were treated with DMSO, 10 nM A6 or co-treated with 10 nM and 25 nM Trequinsin at 37°Cwith 5%CO 2 for 24 h. Then cells were washed once with PBS and harvested by scraping and centrifugation at 800 ⁇ g for 5 min. The harvested cells were washed with PBS and lysed for 30 min on ice in buffer containing 50 mM Tris-Hcl (pH 7.4) , 150mM Nacl, 1mM EDTA, 0.5%Triton X-100.
- Tris-Hcl pH 7.4
- the suspended lysate was cleared by centrifugation at 20,000 ⁇ g for 30 min.
- the 3 ⁇ Flag-HA-SLFN12 (WT or K213R) protein or 3 ⁇ Flag-HA-SLFN12 (WT or K213R) /PDE3A complex was purified by Flag M2 and HA beads and eluted by HA peptide.
- total RNA was extracted from HEK293T cells using RNA extraction kit (TIANGEN) following manufacturer’s protocol.
- RNA was incubated with SLFN12 (WT or K213R) protein or SLFN12 (WT or K213R) /PDE3A complex at room temperature for 30 mins in the presence of ATP. After incubation, RNA was analyzed by electrophoresis.
- HeLa, HeLa (PDE3A -/- ) , or HeLa (SLFN12 -/- ) cells (5 ⁇ 10 6 per mouse) mixed with Matrigel (Corning) were subcutaneously injected into female nude mice (Balb/c-nude, 6–7 week) . Mice were maintained in an animal facility with 12 h light/12 h dark cycles, temperature (22–24°C) , humidity (40–60%) at the National Institute of Biological Sciences, Beijing.
- tumor volumes were calculated as (length ⁇ width 2 ) /2.
- Animal experiments were conducted following the Chinese Ministry of Health national guidelines and performed in accordance with institutional regulations reviewed and approved by the Institutional Animal Care and Use Committee of the National Institute of Biological Sciences.
- Compound A6 shows better tumor growth inhibition than anagrelide
- LC–MS/MS analysis was performed using an Agilent 1290 Infinity UHPLC coupled to an Agilent 6495 Triple Quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode.
- MRM multiple reaction monitoring
- the separation was carried out by a Waters ACQUITY UPLC BEH Amide column (2.1 mm ⁇ 100 mm, 1.7 ⁇ m) , heated at 35°C.
- the mobile phase consisted of water with 25 mM ammonium acetate and 25 mM ammonium hydroxide (A) and acetonitrile (B) with the following gradient: 0–1 min, 85%B; 1–12 min, 85–65%B; 12–12.1 min, 65–40%B; 12.1–15 min, 40%B; 15–15.1 min, 40–85%B; 15.1–20 min, 85%B.
- the flow rate was set at 0.3 mL/min. Overall, 1 ⁇ l sample was injected.
- the MRM transitions were m/z 330.1 ⁇ m/z 118.6 (CE 50V) and m/z 330.1 ⁇ m/z 135.8 (CE 33V) in positive ionization mode.
- the concentration was calculated from external calibration curves constructed using a serial dilution of adenosine 3′, 5′-cyclic monophosphate solutions, ranging from 1 to 500 ng/mL. Data processing was performed with Agilent MassHunter software (Ver. B. 07.00) .
Abstract
Provided herein are polycyclic compounds, compositions, and methods for modulating the PDE3A activity or regulating the interaction of PDE3A/SLFN12. The compounds modulate the PDE3A activity or regulate the interaction of PDE3A/SLFN12, and are useful as antitumor agents.
Description
The field of the invention
The present invention belongs to the chemical field, and in particularly relates to the Anagrelide and its derivatives and the uses thereof in the preparation of pharmaceuticals or pharmaceutical compositions for the treatment of inhibition of tumors.
Cancers continue to be a major global public health problem and is one of the leading causes of death globally, and is responsible for an estimated 10 million deaths annually (WHO) . Despite the availability of anti-tumor agents, including small molecules, and immunomodulatory agents, have been shown to benefit a subset of patients with unique genomic mutations, more general cancer continues to be a significant unmet worldwide medical problem. Current treatments do not provide an ideal cure; drug resistance, low efficacy, and tolerability issues majorly limited the efficacy of these treatments. There is a need in the art for novel therapeutic agents that treat, ameliorate or cure cancer.
The inventors previously identified that human 17-β-estradiol (E2) and its related steroid hormones can bind directly to phosphodiesterase 3A (PDE3A) , which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12) and triggers apoptosis by downregulating the level of Bcl-2 and Mcl-1. Administration of PDE3A or SLFN12-regulating agents, either as monotherapy or in combination with other anti-tumor treatments, will lead to significantly improved anti-cancer therapy, diminished progression of the disease, and enhanced survival rates.
Polycyclic agents, such as Anagrelide (Agrylin/Xagrid) , is a phosphodiesterase inhibitor useful affecting blood cell functions such as proliferation, maturation, and differentiation. It is a drug used for the treatment of essential thrombocytosis (also known as essential thrombocythemia) , or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia. However, functions and mechanisms of these polycyclic compounds in the treatment of tumor have not been well-understood.
Summary of the invention
The present invention relates to novel antitumor compounds, pharmaceutical compositions comprising such compounds, as well as methods of modulating the PDE3A activity or regulating the interaction of PDE3A/SLFN12, thus has potential to be developed as effective antitumor agents.
The objective of the invention is to provide a compound, a composition, and a method for modulating the PDE3A activity or regulating the interaction of PDE3A/SLFN12. Compounds of the present invention modulate the PDE3A activity or regulate the interaction of PDE3A/SLFN12, and are useful as antitumor agents. In addition, the present invention includes methods for preparing the compounds of the invention.
In the first aspect, the present invention provides a compound of Formula (I) or Formula (I’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
Wherein,
R
1, R
2, R
3, R
4, R
5, and R
6 are independently hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl, ; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S, optionally substituted C
1-C
10 alkylamino, optionally substituted C
6-C
10 arylamino, optionally substituted C
3-C
10 cycloalkylamino, optionally substituted-C
1-C
10 alkyl or heteroalkyl, optionally substituted-C
2-C
8 alkenyl or heteroalkenyl, optionally substituted-C
2-C
8 alkynyl or heteroalkynyl and optionally-C
1-C
10 substituted alkoxyl or heteroalkoxyl;
group G is selected from CR
7R
8-, -C (O) -, -O-, -NR
9-, -S-and-S (O)
2-; R
7, R
8 and R
9 are independently selected from hydrogen, halogen, CN, optionally substituted-C
2-C
8 alkyl or heteroalkyl, optionally substituted-C
2-C
8 alkenyl or heteroalkenyl, optionally substituted-C
2-C
8 alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted -C
3-C
8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
group K is selected from CR
10R
11-, -C (O) -, -O-, -NR
12-, -S-and-S (O)
2-; n is 0, 1, 2, 3 or 4; R
10, R
11 and R
12 are independently selected from hydrogen, halogen, CN, optionally substituted -C
2-C
8 alkyl or heteroalkyl, optionally substituted-C
2-C
8 alkenyl or heteroalkenyl, optionally substituted-C
2-C
8 alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted-C
3-C
8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;
X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, -B-, -Se-, -S-, -CR
13R
14-, -NHR
15-, -NR
16R
17-, -O-, -C (O) -, -S (O) -and-S (O)
2-; and R
13, R
14, R
15, R
16 and R
17 at each occurrence are independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyls or heteroalkyl, alkenyl or heteroalkenyl, alkynyl or heteroalkynyl, aryl or heteroaryl, alkoxyl or heteroalkoxyl, including cyclic and substituted forms of each aryl and heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B and Se; and
In some embodiments, the compound of Formula (I) or Formula (I’) is not a compound selected from the following compounds:
In some embodiments, R
1, R
2, R
3, R
4, R
5, and R
6 are independently deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted (C1-C10) alkyl or (C1-C10) heteroalkyl, optionally substituted (C1-C10) aryl or (C1-C10) heteroaryl, optionally substituted (C2-C4) alkenyl or (C6-C8) alkenyl, optionally substituted (C2-C4) alkynyl or (C6-C8) alkynyl, (C1-C6) alkoxyl or (C6-C8) alkoxyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl-SO
2-, (C3-C6) cycloalkyl, or a (C5-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5, and R
6 are independently hydrogen, deuterium, halogen, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy, optionally substituted hydroxy, amino, optionally substituted amino, optionally substituted (C1-C6) alkyl, (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl, (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl -SO
2-, (C3-C6) cycloalkyl, or a (C5-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5 and R
6 are independently hydrogen, deuterium, halogen, hydroxyl or optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl, or (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5 and R
6 are independently hydrogen, deuterium, halogen, hydroxy, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, Si and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5 and R
6 are all hydrogen.
In some embodiments, ring A is hydrophobic.
In some embodiments, ring A is selected from optionally substituted 3-to 6-membered heterocycle and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S. In some embodiments, ring A is selected from optionally substituted 3-to 6-membered aryl or heteroaryl; wherein the heteroatom is selected from the group consisting of N, O and S.
In some embodiments, ring A is selected from optionally substituted-C
5-C
6 cycloalkyl or heterocycle and optionally substituted 5-to 6-membered aryl or heteroaryl; wherein the heteroatom is selected from the group consisting of N, O and S.
In some embodiments, ring A is optionally substituted aryl or heteroaryl group derived from one of the following by removal of one hydrogen atom:
wherein S
m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, ring A is optionally substituted 6-membered aryl or heteroaryl group derived from one of the following by removal of one hydrogen atom:
wherein S
m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, Cl, Br, F, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si and S.
In some embodiments, ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, Cl, Br, F, CN, methyl, ethyl, vinyl and ethynyl.
In some embodiments, G is selected from CR
7R
8-, -C (O) -, -O-, -NR
9-, -S-and-S (O)
2-; R
7 and R
8 are same or different; R
7, R
8 and R
9 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C
2-C
8 alkyl or heteroalkyl, optionally substituted-C
2-C
8 alkenyl or heteroalkenyl, optionally substituted -C
3-C
8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted 3-and 8-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, G is selected from CR
7R
8-, -N-, =N-, -C (O) -, -O-and-NHR
9-; R
7 and R
8 are same or different; R
7, R
8 and R
9 are independently selected from hydrogen, deuterium, halogen, CN, optionally substituted-C
2-C
6 alkyl or heteroalkyl, optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted-C
3-C
6aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, G is CR
7R
8-; R
7 and R
8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted-C
2-C
6 alkyl or heteroalkyl, or optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P and S. In some embodiments, G is CR
7R
8-; R
7 and R
8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S.
In some embodiments, G is CR
7R
8-; R
7 and R
8 are different and independently selected from hydrogen, deuterium and halogen.
In some embodiments, K is selected from CR
10R
11-, -C (O) -, -O-, -NR
12-, -S-and-S (O)
2-; n is 0, 1, 2, 3 or 4; R
10 and R
11 are same or different; R
10, R
11 and R
12 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C
2-C
8 alkyl or heteroalkyl, optionally substituted-C
2-C
8 alkenyl or heteroalkenyl, optionally substituted-C
3-C
8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted 3-and 8-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, K is selected from CR
10R
11-, -N-, =N-, -C (O) -, -O-and-NHR
12-; n is 1, 2 or 3; R
10 and R
11 are same or different; R
10, R
11 and R
12 are independently selected from hydrogen, deuterium, halogen, CN, optionally substituted-C
2-C
6 alkyl or heteroalkyl, optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted-C
3-C
6 aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, K is CR
10R
11-; n is 1, 2 or 3; R
10 and R
11 are same or different; R
10 and R
11 are independently selected from hydrogen, deuterium, halogen, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S.
In some embodiments, K is CR
10R
11-; n is 1, 2 or 3; R
10 and R
11 are same or different; R
10 and R
11 are independently selected from hydrogen, deuterium, halogen and optionally substituted phenyl. In some embodiments, K is CR
10R
11-; n is 1, 2 or 3; R
10 and R
11 are same or different, and independently selected from hydrogen, deuterium and halogen. In some embodiments, K is CR
10R
11-; n is 1, 2 or 3; R
10 and R
11 are different and independently selected from hydrogen, deuterium and halogen.
In some embodiments, B is selected from optionally substituted-C
1-C
6 alkyl or heteroalkyl, optionally substituted-C
2-C
6 alkenyl or heteroalkenyl, optionally substituted-C
2-C
6 alkynyl or heteroalkynyl and optionally-C
1-C
6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is selected from optionally substituted-C
1-C
2 alkyl or heteroalkyl, optionally substituted–C
2-C
3 alkenyl or heteroalkenyl, optionally substituted–C
2-C
3 alkynyl or heteroalkynyl and optionally-C
1-C
2 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is selected from optionally substituted–C
3-C
4 alkyl or heteroalkyl, optionally substituted–C
5-C
6 alkyl or heteroalkyl, optionally substituted–C
4-C
6 alkenyl or heteroalkenyl, optionally substituted–C
4-C
6 alkynyl or heteroalkynyl, optionally –C
3-C
4 substituted alkoxyl or heteroalkoxyl and optionally–C
5-C
6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S; preferably, the optional substitutes are same or different and independently selected from optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is F; G is CR
7R
8-, wherein R
7 and R
8 are different and independently selected from hydrogen and halogen (F, Cl or Br) ; and K is CR
10R
11-, wherein R
9 and R
10 are same or different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3.
In some embodiments, B is Cl; G is CR
7R
8-, wherein R
7 and R
8 are different and independently selected from hydrogen and halogen (F, Cl or Br) ; and K is CR
10R
11-, wherein R
9 and R
10 are different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3.
In some embodiments, B is Br; G is CR
7R
8-, wherein R
7 and R
8 are different and independently selected from hydrogen and halogen (F, Cl or Br) ; and K is CR
10R
11-, wherein R
9 and R
10 are same or different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3.
In some embodiments, n is 1.
In some embodiments, n is 2 and K represent the same group or different groups.
In some embodiments, X, Y, Z, W, and Q are each independently selected from the group consisting of-N-, =O-, =S, -B-, -S-, -CR
13R
14-, -NHR
15-, -NR
16R
17-, -O-, -C (O) -, -S (O) -and -S (O)
2-; and R
13, R
14, R
15, R
16 and R
17 at each occurrence are independently selected from the group consisting of hydrogen, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl, optionally substituted (C3-C6) cycloalkyl and a (C5-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, B, Si, P and S.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O, =S, -B-, -S-, -CR
13R
14-, -NHR
15-, -NR
16R
17-, -O-, -C (O) -, -S (O) -and -S (O)
2-; and R
13, R
14, R
15, R
16 and R
17 at each occurrence are independently selected from optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl-SO
2-, (C3-C6) cycloalkyl, or (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O, =S, -S-, -CR
13R
14-, -NHR
15-, -NR
16R
17-, -O-, -C (O) -, -S (O) -and-S (O)
2-; and R
13, R
14, R
15, R
16 and R
17 at each occurrence are independently selected from optionally substituted (C1-C6) alkyl, (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl, (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, B, Si and S.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, =N-, -O-, -C (O) -, -S (O) -and-S (O)
2-.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, =N-, -S-, -O-, -C (O) -, -S (O) -and-S (O)
2-.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, -B-, -S-, -O-, -C (O) -, -S (O) -and-S (O)
2-.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-, -O-, =S and-S-.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, =N-, -O-and-S-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, R
4, R
5 and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, R
4, R
5, and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, R
4, R
5, and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of -N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
5, and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are combined with other atoms to form optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, and R
4 are independently defined as above.
Preferably, the present invention provides a compound of Formula (II) or Formula (II’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
Wherein,
R
1, R
2, R
3, R
4, R
5 and R
6, ring A, B, X, Y, Z, W and Q are the same as previously defined in the formula (I) or formula (I’) ;
R
a, R
b and R
c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN,hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; and
In some embodiments, the compound of Formula (II) or Formula (II’) is not a compound selected from the following compounds:
In some embodiments, R
1, R
2, R
3, R
4, R
5, R
6, R
a, R
b and R
c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5, R
6, R
a, R
b and R
c are independently selected from hydrogen, deuterium, F, Cl, Br, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5, R
6, R
a, R
b and R
c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5 and R
6 are independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S; and/or R
a, R
b, and R
c are independently selected from hydrogen, deuterium, F, Cl, Br, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
In some embodiments, R
a, R
b, and R
c are independently selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, R
a is halogen (F, Cl or Br) , R
b is selected from hydrogen, deuterium and halogen (F, Cl or Br) , and R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, ring A is hydrophobic.
In some embodiments, ring A is selected from optionally substituted-C
3-C
8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si and S.
In some embodiments, ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 6-membered heterocycle, optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S.
In some embodiments, ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S.
In some embodiments, ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein 6-membered aryl or heteroaryl are derived from one of the following by removal of one hydrogen atom:
Wherein S
m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, ring A is optionally substituted phenyl, wherein the phenyl is derived from the following by removal of one hydrogen atom:
Wherein S
m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si and S.
In some embodiments, ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, Cl, Br, F, CN, methyl, ethyl, vinyl and ethynyl.
In some embodiments, B is selected from optionally substituted-C
1-C
6 alkyl or heteroalkyl, optionally substituted-C
2-C
6 alkenyl or heteroalkenyl, optionally substituted-C
2-C
6 alkynyl or heteroalkynyl and optionally-C
1-C
6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is selected from optionally substituted-C
1-C
2 alkyl or heteroalkyl, optionally substituted–C
2-C
3 alkenyl or heteroalkenyl, optionally substituted–C
2-C
3 alkynyl or heteroalkynyl and optionally-C
1-C
2 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is selected from optionally substituted–C
3-C
4 alkyl or heteroalkyl, optionally substituted–C
5-C
6 alkyl or heteroalkyl, optionally substituted–C
4-C
6 alkenyl or heteroalkenyl, optionally substituted–C
4-C
6 alkynyl or heteroalkynyl, optionally –C
3-C
4 substituted alkoxyl or heteroalkoxyl and optionally–C
5-C
6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S; preferably, the optional substitutes are same or different and independently selected from optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is F; R
a is halogen (F, Cl or Br) ; R
b is selected from hydrogen, deuterium and halogen (F, Cl or Br) ; R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, B is Cl; R
a is halogen (F, Cl or Br) ; R
b is selected from deuterium and halogen (F, Cl or Br) ; R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, B is Br; R
a is halogen (F, Cl or Br) ; R
b is selected from hydrogen, deuterium and halogen (F, Cl or Br) ; R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =N-, =O-, =S, -B-, -S-, -CR
13R
14-, -NHR
15-, -NR
16R
17-, -O-, -C (O) -, -S (O) -and -S (O)
2-; and R
13, R
14, R
15, R
16 and R
17 at each occurrence are independently selected from the group consisting of hydrogen, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl, optionally substituted (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, B, Si, P and S.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, =N-, -O-and-S-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, R
4, R
5, and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, R
4, R
5, and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of -N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, R
4, R
5, and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are each independently selected from the group consisting of, -N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
5, and R
6 are independently defined as above.
In some embodiments, X, Y, Z, W and Q are combined with other atoms to form optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:
wherein R
3, and R
4 are independently defined as above.
Preferably, the present invention provides a compound of Formula (III) or Formula (III’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
Wherein,
R
1, R
2, R
3, R
4, R
5 and R
6, ring A and B are the same as previously defined in the formula (I) , formula (I’) , formula (II) or formula (II’) ;
R
a, R
b and R
c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; and
In some embodiments, the compound of Formula (III) or Formula (III’) is not a compound selected from the following compounds:
In some embodiments, R
1, R
2, R
3, R
4, R
5, R
a, R
b and R
c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5, R
6, R
a, R
b and R
c are independently selected from hydrogen, deuterium, F, Cl, Br, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5, R
a, R
b and R
c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
In some embodiments, R
1, R
2, R
3, R
4, R
5 and R
6 are independently selected from hydrogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S; and/or R
a, R
b, and R
c are independently selected from hydrogen, deuterium, F, Cl, Br, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P and S.
In some embodiments, R
a, R
b, and R
c are independently selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, R
a is halogen (F, Cl or Br) , R
b is selected from hydrogen, deuterium and halogen (F, Cl or Br) , and R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, ring A is hydrophobic.
In some embodiments, ring A is selected from optionally substituted-C
3-C
8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O, P, B, Si and S.
In some embodiments, ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, and S.
In some embodiments, ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 6-membered heterocycle, optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S. In some embodiments, ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S.
In some embodiments, ring A is selected from optionally substituted 6-membered aryl or heteroaryl, wherein 6-membered aryl or heteroaryl are derived from one of the following by removal of one hydrogen atom:
Wherein S
m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, ring A is optionally substituted phenyl, wherein the phenyl is derived from the following by removal of one hydrogen atom:
Wherein S
m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl, or a (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si and S.
In some embodiments, ring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, Cl, Br, F, CN, methyl, ethyl, vinyl and ethynyl.
In some embodiments, substituted phenyl is a phenyl substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 alkyl-amino, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C10 alkenyl, C2-C10 alkenyloxy, C2-C10 alkynyl, C2-C10 alkynyloxy, C1-C10 carboxyl and C1-C10 ester group. In some embodiments, substituted phenyl is a phenyl substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkenyloxy, C2-C6 alkynyl, C2-C6 alkynyloxy, C1-C6 carboxyl and C1-C6 ester group.
In the context of the present disclosure, the term “substituted” means that one or more hydrogens in the described objective (a group or a ring) can be substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen (such as F, Cl, Br, I) , nitro (-NO
2) , amino (NH
2) , C1-C10 alkyl (such as methyl, ethyl, isopropyl, n-propyl, butyl) , C1-C10 alkoxy (such as methoxy, ethoxy, isopropoxy, n-propoxy, butoxy) , C1-C10 haloalkyl (such as CHF
2, CF
3, CH
2CHF
3) , C1-C10 haloalkoxy, C1-C10 alkyl-amino (such as methylamino, ethylamino, propylamino, butylamino) , C6-C10 aryl, C6-C10 aryl-amino, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C10 alkenyl (such as vinyl, allyl) , C2-C10 alkenyloxy, C2-C10 alkynyl, C2-C10 alkynyloxy, C1-C10 carboxyl (such as-COOH) and C1-C10 ester group (such as-COOCH
3, -COOC
2H
5) . For example the one or more substituents are selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C2-C6 alkenyl, C2-C6 alkoxy, C2-C6 alkynyl, C2-C6 alkoxy, C1-C6 carboxyl and C1-C6 ester group. For example the one or more substituents are selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkenyloxy, C2-C6 alkynyl, C2-C6 alkynyloxy, C1-C6 carboxyl and C1-C6 ester group.
In some embodiments, B is selected from optionally substituted-C
1-C
6 alkyl or heteroalkyl, optionally substituted-C
2-C
6 alkenyl or heteroalkenyl, optionally substituted-C
2-C
6 alkynyl or heteroalkynyl and optionally-C
1-C
6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, substituted amino is an amino substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 haloalkyl, C1-C10 haloalkoxy, C1-C10 alkyl-amino, C3-C10 cycloalkyl, C3-C10 cycloalkoxy, C2-C10 alkenyl, C2-C10 alkenyloxy, C2-C10 alkynyl, C6-C10 aryl, C6-C10 aryl-amino, C2-C10 alkynyloxy, C1-C10 carboxyl and C1-C10 ester group. In some embodiments, substituted amino is an amino substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halogen, nitro, amino, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl-amino, C3-C6 cycloalkyl, C3-C6 cycloalkoxy, C2-C6 alkenyl, C2-C6 alkenyloxy, C2-C6 alkynyl, C2-C6 alkynyloxy, C1-C6 carboxyl and C1-C6 ester group.
In some embodiments, B is selected from optionally substituted-C
1-C
2 alkyl or heteroalkyl, optionally substituted–C
2-C
3 alkenyl or heteroalkenyl, optionally substituted–C
2-C
3 alkynyl or heteroalkynyl and optionally-C
1-C
2 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is selected from optionally substituted–C
3-C
4 alkyl or heteroalkyl, optionally substituted–C
5-C
6 alkyl or heteroalkyl, optionally substituted–C
4-C
6 alkenyl or heteroalkenyl, optionally substituted–C
4-C
6 alkynyl or heteroalkynyl, optionally –C
3-C
4 substituted alkoxyl or heteroalkoxyl and optionally–C
5-C
6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S; preferably, the optional substitutes are same or different and independently selected from optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle.
In some embodiments, B is F; R
a is halogen (F, Cl or Br) ; R
b is selected from hydrogen, deuterium and halogen (F, Cl or Br) ; R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, B is Cl; R
a is halogen (F, Cl or Br) ; R
b is selected from deuterium and halogen (F, Cl or Br) ; R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
In some embodiments, B is Br; R
a is halogen (F, Cl or Br) ; R
b is selected from hydrogen, deuterium and halogen (F, Cl or Br) ; R
c is selected from hydrogen, deuterium and halogen (F, Cl or Br) .
Preferably, the present invention provides a compound of Formula (IV) or Formula (IV’) , an isomer, a pharmaceutically acceptable salt or a prodrug, or a formulation thereof:
wherein,
R
1, R
2, R
3, R
4, and R
5, ring A and B are the same as previously defined in the formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) .
In some embodiments, R
a, R
b and R
c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S.
In some embodiments, R
1, R
2, R
3, R
4, and R
5 are hydrogen. In some embodiments, R
a is chloro. In some embodiments, R
c is hydrogen. In some embodiments, R
a is chloro.
In some embodiments, R
1, R
2, R
3, R
4, and R
5 are independently hydrogen, deuterium, C
1-C
6 alkyl, C
6-C
10 aryl, C
3-C
10 heteroaryl; R
a is chloro, R
b and R
c are independently hydrogen, deuterium, C
1-C
6 alkyl, C
6-C
10 aryl, or C
3-C
10 heteroaryl.
In some embodiments, R
b is hydrogen, chlorine, bromine, or fluorine, R
1, R
2, R
3, R
4, and R
5 are independently hydrogen, deuterium, C
1-C
6 alkyl, C
6-C
10 aryl, C
3-C
10 heteroaryl; R
a is chloro, R
b and R
c are independently hydrogen, deuterium, C
1-C
6 alkyl, C
6-C
10 aryl, or C
3-C
10 heteroaryl; and/or ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, and S; B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, and S, optionally substituted-C
1-C
10 alkyl or heteroalkyl, optionally substituted-C
2-C
8 alkenyl or heteroalkenyl, optionally substituted-C
2-C
8 alkynyl or heteroalkynyl and optionally -C
1-C
10 substituted alkoxyl or heteroalkoxyl.
In some embodiments, ring A is selected from optionally substituted-C
3-C
6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, and S.
In some embodiments, B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, and S, optionally substituted C
1-C
10 alkylamino, optionally substituted C
6-C
10 arylamino, optionally substituted C
3-C
10 cycloalkylamino, optionally substituted-C
1-C
10 alkyl or heteroalkyl, optionally substituted-C
2-C
8 alkenyl or heteroalkenyl, optionally substituted-C
2-C
8 alkynyl or heteroalkynyl and optionally-C
1-C
10 substituted alkoxyl or heteroalkoxyl.
In some embodiments, the compound of Formula (IV) or Formula (IV’) is not a compound selected from the following compounds:
Each preferred group stated above can be taken in combination with one, any or all other preferred groups, and the pharmaceutically acceptable salts or prodrug thereof.
In some embodiments, the compounds are selected from the group consisting of the followings:
It will be appreciated that the description of the present invention herein should be construed in congruity with the laws and principles of chemical bonding. In some instances, it may be necessary to remove a hydrogen atom in order to accommodate a substituent at any given location.
It will be yet appreciated that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
It will be yet appreciated that the compounds of the present invention may contain one or more isotopic forms, either hydrogen isotopic forms of D or T, or isotopic isoform of any atoms, such as C, N, P, or S. All isotopic forms are contemplated to be within the scope of the present invention.
The polycyclic compounds of the present invention act as molecular glue to form a stable ternary complex with PDE3A and SLFN12, and interact more favorably with the interfacial residues of SLFN12. It was found that the polycyclic compounds of the present invention were engaged in the hydrophobic interaction with Thr844, Phe972, Leu910 in PDE3A and Ile557, Ile558 in SLFN12 in a structure-effect analysis. This is a critical interaction. It is further found that these compounds are significantly stronger compared with the Anagrelide analogue. Especially, compounds with ring A, especially the hydrophobic ring A, perform much better than those with hydrophilic group at the same position.
In a second aspect, the present invention provides a pharmaceutical composition containing the compound of the formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) , formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts and/or prodrug thereof, and also containing at least one pharmaceutically acceptable diluents, excipients or carriers.
Preferably, the pharmaceutical composition is in a form suitable for oral, topical, transdermal, injection, rectal or inhalation administration, especially in the form of tablets, capsules, solutions, liquids, gels, ointments, syrup, spray, nebulizer or suppositories.
In a third aspect, the present invention provides compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for use as PDE3A modulator and/or SLFN12 modulator.
Preferably, the modulator is capable of inhibiting, disrupting and/or accelerating the activity of PDE3A and/or the activity of SLFN12.
In a forth aspect, the present invention provides compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for use as chemicals regulating PDE3A and SLFN12 interaction.
Preferably, the chemical is capable of enhancing and/or promoting the interaction of PDE3A and SLFN12.
In a fifth aspect, the present invention provides use of compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for the manufacture of a medicament to treat or prevent a disease or disorder associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12.
In a sixth aspect, the present invention provides use of compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition for the treatment or prevention of a disease or disorder associated with cancer or tumor, preferably for treatment or inhibition of tumor and/or inhibition of growth of tumor cells.
Preferably, the cancer or tumor is selected from Leukemia, lymphoma, myelodysplastic syndrome or myeloma, preferably selected from acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute T-cell leukemia, acute lymphoblastic leukaemia (all) , chronic lymphoblastic leukemia (CLL) , acute monocytic leukemia (amol) , mantle cell lymphoma (MCL) , B-cell lymphoma Histiocytic lymphoma or multiple myeloma.
Preferably, the cancer or tumor is selected from: adenocarcinoma, squamous cell carcinoma, adenosarcoma, undifferentiated carcinoma, large cell carcinoma or small cell carcinoma, hepatocellular carcinoma, hepatoblastoma, colon adenocarcinoma, renal cell carcinoma, renal cell adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, glioblastoma, glioma, head and neck cancer, lung cancer, breast cancer, Merkel cell carcinoma, rhabdomyosarcoma, malignant melanoma, Epidermoid carcinoma, lung cancer, renal cancer, adenocarcinoma of the breast, breast cancer, breast cancer, breast cancer, non-small cell lung cancer, ovarian cancer, oral cancer, anal cancer, skin cancer, Ewing's sarcoma, gastric cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Villum's tumor, Walden West Len's globulinemia, pancreatic cancer, pancreatic adenocarcinoma, cervical cancer, squamous cell carcinoma, medulloblastoma, prostate cancer, Malignant tumor or metastatic induced secondary tumor of colon cancer, colon adenocarcinoma, transitional cell carcinoma, osteosarcoma, ductal carcinoma, large cell lung cancer, small cell lung cancer, ovarian adenocarcinoma, ovarian teratoma, bladder papilloma, neuroblastoma, glioblastoma multiforme, glioblastoma, astrocytoma, epithelioid carcinoma, melanoma or retinoblastoma.
Preferably, the cancer is associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12.
In a seventh aspect, the present invention provides a method for preventing or treating a disease or disorder associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12, comprising administering to a subject in need thereof compounds of formula (I) , formula (II) , formula (III) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof or the pharmaceutical composition according to the present invention.
In an eighth aspect, the present invention provides a method for preventing or treating a disease or disorder of cancer or tumor, comprising administering to a subject in need thereof compounds of formula (I) , formula (I’) , formula (II) , formula (II’) , formula (III) or formula (III’) , formula (IV) or formula (IV’) , pharmaceutically acceptable salts or prodrug thereof and/or the pharmaceutical composition according to the present invention.
The present invention features improved methods of identifying patients having cancer (e.g., melanoma, endometrium, lung, hematopoetic/lymphoid, ovarian, cervical, soft tissue sarcoma, leiomyosarcoma, urinary tract, pancreas, thyroid, kidney, glioblastoma and/or breast cancer) that is sensitive to treatment with the compounds in the present invention in modulating the function of PDE3A or the interaction of PDE3A/SLFN12 in a cancer cell derived from such patients.
In some embodiment, the compounds described herein are suitable for monotherapy and are effective against cancer.
In some embodiment, the compounds described herein are suitable for use in combination therapy. The additional therapeutic agent could be selected from immune modulator or immune stimulator therapies, which includes but not limited to PD-1, PD-L1 or other CAR-T therapies. The compound and the additional therapeutic agent could be co-administered or administered separately.
In some embodiment of the combination therapy, administering the compound of the invention allows for administering of the additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating cancer in an individual in need thereof.
It should be understood that the compounds encompassed by the present invention are those that are suitably stable for use as pharmaceutical agent.
Brief description of the figures
Figure 1. Compound A0 induced cell death in HeLa cells dependents on PDE3A and SLFN12. HeLa, HeLa (PDE3A
-/-) and HeLa (SLFN12
-/-) cells were treated with A0 at the indicated concentration for 48 h. Cell viability was determined by measuring ATP levels. Data are represented as mean±SD of triplicate wells.
Figure 2. Compound A6 induced cell death in HeLa cells dependents on PDE3A and SLFN12. HeLa, HeLa (PDE3A
-/-) and HeLa (SLFN12
-/-) cells were treated with A6 at the indicated concentration for 48 h. Cell viability was determined by measuring ATP levels. Data are represented as mean±SD of triplicate wells.
Figure 3. Compound A6 shows tumor growth inhibitory effect. a: Female BALB/c-Nude mice subcutaneously inoculated with HeLa cells. After 7 days, the mice were treated with Vehicle, Anagrelide (5 mg/kg) , A6 (5 mg/kg) , or A6 (1 mg/kg) by oral gavage. Shown are representative photos of mice on day 21. b Typical photos of tumors from the Vehicle, Anagrelide (5 mg/kg) , A6(5 mg/kg) , or A6 (1 mg/kg) treated mice. Mice were sacrifificed after treatment for 21 days; tumors were dissected and photographed. c The tumor growth curves of the tumor-burdened mice. Tumor measurements were performed three times a week using calipers; the average tumor volume±SD for each cohort is displayed (n=5/group) . Student’s t-test (two-tailed, unpaired) was performed, ns not signifificant, *p<0.05, **p<0.01, ***p<0.001 for comparisons of A6 (5 mg/kg) -, anagrelide (5 mg/kg) -, or A6 (1 mg/kg) -treated group with untreated group (vehicle) . d Body weight curves of the tumor-burdened mice. The average body weight±SD for each cohort is displayed (n=5/group) .
Definitions and details description of the invention
For the purposes of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa. It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. The invention is not restricted to the details of any embodiment.
The terms "comprising" , "containing" , "having" , and "including" are to be construed as open-ended terms (i.e., meaning "including, but not limited to" ) unless otherwise noted.
The term "pharmaceutically acceptable salt or prodrug" of a compound means a salt that is pharmaceutically acceptable and that it possesses the desired pharmacological activity of the parent compound.
The terms "subject" and "patient" are used herein interchangeably and refer to mammals, in particular humans.
The term "aryl, " as used herein, refers to a mono-or polycyclic carboring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polyring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused ring, covalently attached ring or a combination thereof. The term "heteroaryl, " as used herein, refers to a mono-or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused ring, covalently attached ring or a combination thereof. In accordance with the invention, aromatic groups can be substituted or unsubstituted.
The term “cyclic aryl” or “cyclic heteroaryl” refers to a ring system consisting of two ring wherein at least one ring is aromatic; and the two ring can be fused or covalently attached.
The term “alkyl” as used herein, refers to saturated, straight-or branched-chain hydrocarbyl radicals. "Ci-Cs alkyl, ” “Ci-Ce alkyl, ” “Ci-Cio alkyl” “C2-C4 alkyl, ” or “C3-C alkyl, ” refer to alkyl groups containing from one to three, one to six, one to ten carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively. Examples of Ci-Ce alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, <<-butyl, tert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
The term “alkenyl” as used herein, refers to straight-or branched-chain hydrocarbyl radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom. “C2-C10 alkenyl, ” “C2-C8 alkenyl, ” “C2-C4 alkenyl, ” or “C3-C6 alkenyl, ” refer to alkenyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl, and the like.
The term “alkynyl” as used herein, refers to straight-or branched-chain hydrocarbyl radicals having at least one carbon-carbon triple bond by the removal of a single hydrogen atom. “C2-C10 alkynyl, ” “C2-C8 alkynyl, ” “C2-C4 alkynyl, ” or “C3-C6 alkynyl, ” refer to alkynyl groups containing from two to ten, two to eight, two to four or three to six carbon atoms respectively. Representative alkynyl groups include, but are not limited to, ethynyl, l-propynyl, l-butynyl, heptynyl, octynyl, and the like.
The term “cycloalkyl” , as used herein, refers to a monocyclic or polycyclic saturated carboring or a bi-or tri-cyclic group fused, bridged or spiro system, and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocyclic olefmic, iminic or oximic double bond. Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. Examples of C3-C12 cycloalkyl include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo [2.2. l] heptyl, bicyclo [3. l. 0] hexyl, spiro [2.5] octyl, 3-methylenebicyclo [3.2. l] octyl, spiro [4.4] nonanyl, and the like. The term “cycloalkenyl” , as used herein, refers to monocyclic or polycyclic carboring or a bi-or tri-cyclic group fused, bridged or spiro system having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted or optionally substituted with exocycbc olefmic, iminic or oximic double bond. Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups. Examples of C3-C12 cycloalkenyl include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo [2.2. l] hept-2-enyl, bicyclo [3. l. 0] hex-2-enyl, spiro [2.5] oct-4-enyl, spiro [4.4] non-lenyl, bicyclo [4.2. l] non-3-en-9-yl, and the like. As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CEhCEh-phenyl.
The term “substituted” refers to one or more hydrogen atoms in the group are Substituted by one or more substituents selected from the group consisting of C1-C10 alkyl group, C3-C10 cycloalkyl group, C1-C10 alkoxy, halogengen, hydroxy, carboxyl, C1-C10 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, and phenyl group;
The term “substituted heteroarylalkyl” means a heteroarylalkyl functional group in which the heteroaryl group is substituted. As used herein, the term “alkoxy” employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, l-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy are (C1-C3) alkoxy. It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
The terms “heterocyclic” or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi-or tri-cyclic group fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quatemized, (v) any of the above ring may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxosubstituted or optionally substituted with exocyclic olefmic, iminic or oximic double bond. Representative heterocycloalkyl groups include, but are not limited to, l, 3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo [2.2. l] -heptyl, 8-azabicyclo [3.2. l] octyl, 5-azaspiro [2.5] octyl, l-oxa-7-azaspiro [4.4] nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible) . It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom (s) . One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
The term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, deuterium, tritium, -F, -Cl, -Br, -I, -OH, Alkyls, aryls
The term “halogen” or “halogengen” alone or as part of another substituents, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom. The term “optionally substituted” , as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group (s) individually and independently selected from groups described herein.
The term “hydrogen” includes hydrogen and deuterium. In addition, the recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable. In certain embodiments, the compounds of each formula herein are defined toinclude isotopically labelled compounds. An “isotopically labelled compound” is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level which is significantly greater than the natural abundance of that isotope. For example, one or more hydrogen atom positions in a compound can be enriched with deuterium to a level which is significantly greater than the natural abundance of deuterium, for example, enrichment to a level of at least 1%, preferably at least 20%or at least 50%. Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analog, and therefore exhibit a longer half-life when administered to a subject. Such compounds can synthesize using methods known in the art, for example by employing deuterated starting materials. Unless stated to the contrary, isotopically labelled compounds are pharmaceutically acceptable.
The term “hydroxy protecting group, ” as used herein, refers to a labile chemical moiety which is known in the art to protect a hydroxy group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the hydroxy protecting group as described herein may be selectively removed.
The term "protected hydroxy, " as used herein, refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
The term “amino protecting group, ” as used herein, refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure (s) the amino protecting group as described herein may be selectively removed.
The term “protected amino, ” as used herein, refers to an amino group protected with an amino protecting group as defined above.
The term “subject, ” as used herein, refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, and the like.
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system) , increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
The compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R) -or (S) -, or as (D) -or (L) -for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et a, Enantiomers. Racemates and Resolutions (John Wiley&Sons, 1981) . When the compounds described herein contain olefmic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the componds include both E and Z geometric isomers or cis-and tran s isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be in cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbonheteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
As used herein, the term "pharmaceutically acceptable salt, " refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, etal. Describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977) . The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate. As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include but are not limited to, esters of Ci-C6-alkanoic acids, such as acetate, propionate, butyrate and pivalate esters.
The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more pharmaceutically acceptable carriers or excipients.
The term "pharmaceutically acceptable diluents, excipients or carriers" as used herein refers to diluents, excipients or carriers that are suitable for use with humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate with a reasonable benefit/risk ratio. "Diluents" are agents which are added to the bulk volume of the active agent making up the solid composition. "Excipients" can be binders, lubricants, glidants, coating additives or combinations thereof. "Carriers" can be solvents, suspending agents or vehicles, for delivering the instant compounds to a subject. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
According to some embodiments, the carriers comprise one or more of phosal 50 propylene glycol (PG) , polyethylene glycol (PEG) 400, PEG300, DMSO, ehanol, and Tween 80.
According to some embodiments, the compound of the present invention is formulated for oral dosing in phosal 50 propylene glycol (PG) , polyethylene glycol (PEG) 400 and ethanol. According to some embodiments, the compound of the present invention is formulated for oral dosing in 40-65%phosal 50 propylene glycol (PG) , 10-40%polyethylene glycol (PEG) 400 and 5-15%ethanol. According to some embodiments, the compound of the present invention is formulated for oral dosing in 50-65%phosal 50 propylene glycol (PG) , 20-30%polyethylene glycol (PEG) 400 and 5-15%ethanol.
According to some embodiments, the compound of the present invention is formulated for oral dosing in phosal 50 propylene glycol (PG) , polyethylene glycol (PEG) 400 and DMSO. According to some embodiments, the compound of the present invention is formulated for oral dosing in 40-65%phosal 50 propylene glycol (PG) , 30-40%polyethylene glycol (PEG) 400 and 2-5%DMSO.
According to some embodiments, the compound of the present invention is formulated for example for oral dosing in formulation: DMSO, PEG300, and Tween80. According to some embodiments, the compound of the present invention is formulated in formulation: 2-5%DMSO, 30%PEG300, 2-5%Tween80.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils) , glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactidepolyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides) . Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient (s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
For pulmonary delivery, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system. Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al, U.S. Pat. No. 5,508,269 to Smith et al, and WO 98/43650 by Montgomery, all of which are incorporated herein by reference) .
An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. According to the methods of treatment of the present invention, viral infections, conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result. By a "therapeutically effective amount" of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect) . An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound (s) of this invention per day in single or multiple doses. The compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5%to about 95%active compound (w/w) . Alternatively, such preparations may contain from about 20%to about 80%active compound. Lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician. Upon improvement of a patient’s condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms. When the compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95%of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. The said “additional therapeutic or prophylactic agents” includes but not limited to, immune therapies (eg. interferon) , therapeutic vaccines, antifibrotic agents, anti inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline) , mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists) , anti-oxidants (e.g. N-acetylcysteine) , cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (e.g. ribavirin and amantidine) . The compositions according to the invention may also be used in combination with gene replacement therapy.
Abbreviations
Abbreviations which may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBN for azobisisobutyronitrile; BINAP for 2, 2’-bis (diphenylphosphino) -l, r-binaphthyl; Boc
2O for di-//-butyl-dicarbonate: Boc for/-butoxy carbonyl; Bpoc for 1-methyl-1- (4-biphenylyl) ethyl carbonyl; Bz for benzoyl; Bn for benzyl; BocNHOH for tert-butyl Nhydroxy carbamate; t-BuOK for potassium/-butoxide: BmSnH for tributyltin hydride; BOP for (benzotriazol-l-yloxy) tris (dimethylamino) phospho-nium Hexafluorophosphate; Brine for sodium chloride solution in water; BSA for N, O-bis- (trimethylsilyl) acetamide; CDI for carbonyldiimidazole; CH
2Cl
2 and DCM for dichloromethane; CH
3 for methyl; CH
3CN for acetonitrile; Cs
2CO
3 for cesium carbonate; CuCl for copper (I) chloride; CuI for copper (I) iodide; dba for dibenzylidene acetone; dppb for diphenylphos-phinobutane; DBU for l, 8-diazabicyclo [5.4.0] -undec-7-ene; DCC for N, N’-dicyclohexyl-carbodiimide; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or (i-Pr)
2EtN for N, N, -diisopropylethyl amine; Dess-Martin periodinane for 1, 1, 1-tris (acetyloxy) -l, l-dihydro-l, 2-benziodoxol-3- (lH) -one; DMAP for 4-dimethylaminopyridine; DME for l, 2-dimethoxy ethane; DMF for N, N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT for di (/>methoxyphenyl) -phenyl methyl or dimethoxytrityl; DPPA for diphenylphosphoryl azide; EDC for N- (3-dimethylaminopropyl) -N’-ethylcarbodiimide; EDC HC1 for N- (3-dimethylaminopropyl) -N’-ethylcarbodiimide hydrochloride; EtOAc for ethyl acetate; EtOH for ethanol; Et
2O for diethyl ether; HATU for 0- (7-azabenzotriazol-l-yl) -N, N, N’, N’, -tetramethyluroniumHexafluoro-phosphate; HC1 for hydrogen chloride; HOBT for 1-hydroxy benzotriazole; K
2CO
3 for potassium carbonate; <<-BuLi for <<-butyl lithium; z-BuLi for/-butyl lithium; /-BuLi for/-butyl lithium; PhLi for phenyl lithium; LDA for lithium diisopropylamide; LiTMP for lithium 2, 2, 6, 6-tetramethyl-piperidinate; MeOH for methanol; Mg for magnesium; MOM for methoxymethyl; Ms for mesyl or-SO
2-CH
3; MS
2O for methanesulfonic anhydride or mesyl-anhydride; MTBE for t-butyl methyl ether; NaN (TMS)
2 for sodium bis (trimethylsilyl) amide; NaCl for sodium chloride; NaH for sodium hydride; NaHCO
3 for sodium bicarbonate or sodium hydrogen carbonate; Na
2CO
3 for sodium carbonate; NaOH for sodium hydroxide; Na
2SO
4 for sodium sulfate; NaHSCb for sodium bisulfite or sodium hydrogen sulfite; Na
2S
2O
3 for sodium thiosulfate; NH
2NH
2 for hydrazine; NH
4HCO
3 for ammonium bicarbonate; NFECl for ammonium chloride; NMO for N-methyl-morpholine N-oxide; NalCri for sodium periodate; Ni for nickel; NSFI for N-fluorobenzene sulfonimide; OH for hydroxy; o/n for overnight; OsO
4 for osmium tetroxide; PTSA for ptoluenesulfonic acid; PPTS for pyridinium/Moluenesulfonate: TBAF for tetrabutylammonium fluoride; TEA or E N for triethylamine; TES for triethylsilyl; TESC1 for triethylsilyl chloride; TESOTf for triethylsilyl trifluoro-methanesulfonate; TFA for trifluoroacetic acid; THF for tetrahydro-furan; TMEDA for N, N, N’, N’-tetramethylethylene-diamine; TPP or PPh
3 for triphenyl-phosphine; Troc for 2, 2, 2-trichloroethyl carbonyl; Ts for tosyl or-SO
2-C
6H
4CH
3; TS
2O for tolylsulfonic anhydride or tosyl-anhydride; TsOH for p-tolylsulfonic acid; Pd for palladium; Ph for phenyl; POPd for dihydrogen dichlorobis (di-tert-butylphosphinito-KP) palladate (II) ; Pd
2 (dba)
3 for tris (dibenzylideneacetone) dipalladium (0) ; Pd (PPh
3)
4 for tetrakis (triphenylphosphine) palladium (0) ; PdCh (PPh
3)
2 for trans-dichlorobis- (triphenylphosphine) palladium (II) ; Pt for platinum; Rh for rhodium; rt for room temperature; Ru for ruthenium; SFC for supercritical fluid chromatography; TBS for t-butyl dimethylsilyl; TMS for trimethylsilyl; or TMSCl for trimethylsilyl chloride.
Synthetic Methods
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes that illustrate the methods by which the compounds of the invention may be prepared. These schemes are of illustrative purpose, and are not meant to limit the scope of the invention. Equivalent, similar, or suitable solvents, reagents or reaction conditions may be substituted for those particular solvents, reagents, or reaction conditions described herein without departing from the general scope of the method of synthesis.
All references cited herein, whether in print, electronic, computer readable storage media or other form, are expressly incorporated by reference in their entirety, including but not limited to, abstracts, articles, journals, publications, texts, treatises, internet web sites, databases, patents, and patent publications. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those associated with the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
Although the invention has been described with respect to various preferred embodiments, it is not intended to be limited thereto, but rather those skilled in the art will recognize that variations and modifications may be made therein which are within the spirit of the invention and the scope of the appended claims.
Examples
The compounds and processes of the present invention will be better understood in connection with the following examples, which are intended as an illustration only and not limiting of the scope of the invention. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art and such changes and modifications including, without limitation, those associated with the chemical structures, substituents, derivatives, formulations and/or methods of the invention may be made without departing from the spirit of the invention and the scope of the appended claims.
Experimental Examples
The examples herein are provided by way of illustration only and not by way of limitation. Those skilled in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes.
Synthesis Methods
Chemical Synthesis. All reactions were carried out under an atmosphere of nitrogen in flame-dried glassware with magnetic stirring unless otherwise indicated. Commercially obtained reagents were used as received. Solvents were dried by passage through an activated alumina column under argon. Liquids and solutions were transferred via syringe. All reactions were monitored by thin-layer chromatography with E. Merck silica gel 60 F254 pre-coated plates (0.25 mm) . 1H and 13C NMR spectra were recorded on Varian Inova-400 or 500 spectrometers. Data for 1H NMR spectra are reported relative to CDCl3 (7.26 ppm) , CD
3OD (3.31 ppm) , or DMSO-d6 (2.50 ppm) as an internal standard and are reported as follows: chemical shift (δppm) , multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, sept=septet, m=multiplet, br= broad) , coupling constant J (Hz) , and integration. Data for 13C NMR spectra are reported relative to CDCl
3 (77.23 ppm) , CD
3OD (49.00 ppm) or DMSO-d6 (39.52 ppm) as an internal standard and are reported in terms of chemical shift (δppm) . Samples preparation and purity analysis were conducted on Waters HPLC (Column: XBridge C18, 5μm, 19 x 150 mm) with 2998PDA and 3100MS detectors, and Waters UPLC (Column: BEH C18, 1.7μm, 2.1 x 50 mm) with PDA and SQD MS detectors, using ESI as ionization. HRMS data were obtained on a Thermo Q Exactive.
All new compounds were synthesized as indicated in detail in the following schemes. Compound A2 was synthesized according to the same synthetic route as compound A1 using different starting materials 3-fluoro-2-chlorobenzaldehyde. Di-substituted compounds A3, A4, A6-A14, A16, A18-A22, A33-A36, A41-A44, A47-A61 were synthesized using a Suzuki coupling reaction from A1. Di-substituted compounds A24-A29, A37, A39, A45, A46 were synthesized according to the synthetic route as compound A23 with different amine compounds. A30, A31, A32, A38, A40 were salt form of compounds A29, A6, A28, A37, A39. Compounds A5 were synthesized according to the same synthetic route as compound A17 using different starting materials 3, 4, 5-trichloroaniline. Tri-substituted compound A15 was synthesized using a Suzuki coupling reaction from A17. A14 was the by-product of the Suzuki coupling reaction for di-substituted compounds.
Scheme 1. Synthesis of di-substitution compounds
Synthesis of compound 2
In a flame-dried 50 mL 2-necked round-bottom flask, concentrated sulfuric acid (15mL) , and 3-bromo-2-chlorobenzaldehyde (2g, 9.11mmol, 1.0equiv) was added in small portions while stirring. Conc. nitric acid (3.0mL) was added dropwise at 0℃. The reaction mixture was stirred at 0 ℃ for 30min and then warmed to rt overnight. It was checked by TLC until completion. The reaction mixture was poured into 100mL ice water, the mixture was extracted with EA (3 x 50 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=300: 1) to give compound 2 as a white solid (1.1g, 46%yield) .
Synthesis of compound 3
In a flame-dried 50 mL round-bottom flask, compound 2 (1.1g, 4.18mmol, 1.0equiv) was dissolved in methanol (20.0mL) . The reaction mixture was cooled to 0℃. NaBH
4 (316mg, 8.36mmol, 2.0equiv) was added in small portions. The reaction mixture was stirred at 0 ℃ for 30min. TLC showed the starting material was consumed. The reaction mixture was quenched with ice water (50mL) , extracted with EA (3 x 50 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=15: 1) a to give compound 3 as a white solid (1.1g, 99%yield) .
Synthesis of compound 4
In a flame-dried 50 mL round-bottom flask, compound 3 (1.1g, 4.15mmol, 1.0equiv) was dissolved in dry DCM (11.0mL) , then dry Et
3N (0.87mL, 6.23mmol, 1.5equiv) was added. The mixture was cooled to 0℃. Methanesulfonyl chloride (0.38mL, 4.98mmol, 1.2equiv) was added in small portions. The reaction mixture was stirred at 0 ℃ for 30min. TLC showed the starting material was consumed. The reaction mixture was quenched with ice water (50mL) , extracted with EA (3 x 50 mL) , washed with Sat. NaHCO
3 and brine and then concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=10: 1) to give compound 4 as a white solid (1.35g, 95%yield) .
Synthesis of compound 5
In a flame-dried 50 mL round-bottom flask, compound 4 (1.35g, 3.94mmol, 1.0equiv) , glycine ethyl ester hydrochloride (825mg, 5.91mmol, 1.5equiv) , were dissolved in dry DMF (27.0mL) , and then dry Et
3N (1.37mL, 9.85mmol, 2.5equiv, ) was added. The reaction mixture was stirred at 90℃ for 14h. TLC showed the starting material was consumed. The reaction mixture was quenched with ice water (50mL) , extracted with EA (3 x 50 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=10: 1) to give compound 5 as a white solid (1.15g, 83%yield) .
Synthesis of compound 6
In a flame-dried 100 mL 2-necked round-bottom flask, Conc. HCl (23mL) , and compound 5 (1.15g, 3.27mmol, 1.0equiv) was added in small portions. Stannous chloride (3.1g, 16.35mmol, 5.0equiv) dissolved in Conc. HCl (13mL) was added dropwise at rt. The reaction mixture was stirred at 40 ℃ for 1h and checked by TLC. The reaction mixture was poured into 100mL ice water (with 35mL NH
3
. H
2O) , extracted with EA (3 x 50 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=15: 1) to give compound 6 as a white solid (913mg, 87%yield) .
Synthesis of compound 7
In a flame-dried 50 mL round-bottom flask, compound 6 (913mg, 2.85mmol, 1.0equiv) was dissolved in dry toluene (20.0mL) , and then cyanogen bromide (453mg, 4.28mmol, 1.5equiv) added in small portions while stirring at rt. The reaction mixture was stirred at 110 ℃ for 14h. It was checked by TLC until completion. The reaction mixture was filtered by sand core funnel to get the crude product 7 as a solid (1.02g) .
Synthesis of compound A1
In a flame-dried 50 mL 2-necked round-bottom flask, compound 7 (1.02g, 2.95mmol, 1.0equiv) and triethylamine (0.61mL, 4.42mmol, 1.5equiv) were dissolved in ethanol (15.0mL) at rt. The reaction mixture was stirred at 100 ℃ for 14h. It was checked by TLC until completion. The reaction mixture was purified by flash chromatography on silica gel (DCM: MeOH=20: 1) to get the product A1 as a off-white solid (729mg) .
Synthesis of compounds A3, A4, A6-A14, A16, A18-A22, A33-A36, A41-A44, A47-A61
In a flame-dried 25 mL tube, A1 (100mg, 0.334mmol, 1.0equiv) , boronic acid (0.40mmol, 1.2equiv) , Cs
2CO
3 (436mg, 1.34mmol, 4.0equiv) , and Pd (dppf) Cl
2 (36.6mg, 0.05mmol, 0.15equiv) were dissolved in dioxane/H
2O (4: 1, 10mL) . The mixture was degassed and filled with argon. The reaction mixture was stirred at 100 ℃ for 5h. It was checked by TLC until completion. The reaction mixture was purified by flash chromatography on silica gel (DCM: MeOH=20: 1) to give the product A3, A4, A6-A14, A16, A18-A22, A33-A36, A41-A44, A47-A61.
Synthesis of compound 9
A flame-dried 250 mL round-bottom flask 4-bromo-3, 5-dichloroaniline (1.0g, 5.13mmol, 1.0equiv) was dissolved in 70.0mL H
2O, and then chloral hydrate (1.7g, 9.09mmol, 1.8equiv) , hydroxylamine hydrochloride (2.0g, 8.57mmol, 5.6equiv) , crystallized sodium sulfate (2.5g, 17.60mmol, 3.2equiv) , and concentrated hydrochloric acid (0.8mL) were added. The reaction mixture was stirred at 80 ℃ for 4h. The reaction mixture was cooled to 0 ℃ and the sediments filtered to get the crude product 9 (1.36g, 85%yield) was used directly without further purification.
Synthesis of compound 10
A flame-dried 50 mL round-bottom flask, compound 9 (1.36g, 4.36mmol, 1.0equiv) and concentrated sulfuric acid (10.0mL) was added. The reaction mixture was stirred at 80 ℃ for 1h. Then the reaction mixture was cooled to room temperature and poured upon ten to twelve times its volume of cracked ice. The mixture was filtered, washed 5 times with cold water to remove the sulfuric acid, and then dried. The crude reaction mixture was purified by flash chromatography on silica gel (PE: EA=15: 1) to give the compound 10 as a brown solid (0.93g, 72%yield) .
Synthesis of compound 11
A flame-dried 50 mL round-bottom flask, compound 10 (0.93g, 3.15mmol, 1.0equiv) , 5 M aqueous sodium hydroxide solution (3.0 mL) were added, and then hydrogen peroxide (30%) solution (1.2 mL) was dropwise over 5min. The reaction mixture was stirred at room temperature for 4h. The concentrated hydrochloric acid was added to adjust the pH to 5-6. The reaction mixture extracted with EA (3 x 100 mL) , washed with brine and then concentrated to give the crude product 11 (870mg) was used directly without further purification.
Synthesis of compound 12
A flame-dried 25 mL round-bottom, compound 11 (770mg, 2.71mmol, 1.0equiv) was dissolved in tetrahydrofuran (10 mL) , and then lithium aluminum hydride (141mg, 3.71mmol, 1.4equiv) in 20 mL tetrahydrofuran was added in portion at 0 ℃. The reaction mixture was stirred at 0 ℃ for 30min before it was gradually warmed to rt overnight. The reaction mixture was poured into 10 mL ice saturated sodium bicarbonate solution, extracted with EA (3 x 100 mL) washed with brine and then concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=10: 1) to give compound 12 as a light yellow solid (510mg, 70%yield) .
Synthesis of compound 13
A flame-dried 25 mL round-bottom flask, compound 12 (40mg, 0.15mmol, 1.0equiv) was dissolved in dichloromethane (5 mL) , and then manganese oxide (80mg, 0.92mmol, 6.1equiv) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was filtered by diatomaceous earth with suction and washed by dichloromethane. The crude mixture was purified by flash chromatography on silica gel to give the compound 13 as a light yellow solid (36mg, 90%yield) .
Synthesis of compound 14
A flame-dried 25 mL round-bottom flask, compound 13 (64mg, 0.24mmol, 1.0equiv) was dissolved in methanol (7 mL) , glycine ethyl ester hydrochloride (40mg, 0.28mmol, 1.2equiv) and sodium cyanoborohydride (18mg, 0.28mmol, 1.2equiv) was added. The reaction mixture was stirred at 35 ℃ for overnight. The reaction mixture was poured into 10 ml ice saturated sodium bicarbonate solution, extracted with EA (3 x 300 mL) washed with brine and then concentrated. The crude reaction mixture was purified by flash chromatography on silica gel (PE: EA=5: 1) to give the compound 14 as a white solid (47mg, 57%yield) .
Synthesis of compound 15
A flame-dried 25 mL round-bottom flask, compound 14 (47mg, 0.13mmol, 1.0equiv) was dissolved in dry toluene (1.3 mL) , and then cyanogen bromide (46mg, 0.40mmol, 3.0equiv) was added in small portions while stirring at rt. The reaction mixture was stirred at rt overnight. The reaction mixture was filtered by sand core funnel (washed with dry toluene) to give the compound 15 as a white solid (36mg, 71%yield) .
Synthesis of compound A17
A flame-dried 50 mL 2-necked round-bottom flask, compound 15 (36mg, 0.09mmol, 1.0equiv) and triethylamine (17μL, 0.12mmol, 1.3equiv) were dissolved in ethanol (1.5 mL) at rt. The reaction mixture was stirred at 80 ℃ for 2.5 h. The reaction mixture was filtered by sand core funnel (washed by ethanol) to give the product A17 as a light yellow solid (12mg, 38%yield) .
Synthesis of compound A15
A flame-dried 10 mL sealed tube, A17 (5.5mg, 0.016 mmol, 1.0 equiv) , phenylboronic acid (2.4mg, 0.019mmol, 1.2equiv) , caesium carbonate (21.4mg, 0.066mmol, 4.0equiv) , Pd (dppf) Cl2 (1.8mg, 0.002mmol, 0.15equiv) were dissolved in dioxane/H
2O (4: 1, 1.0mL) , sealed, degassed and filled with argon. The reaction mixture was heated to 100 ℃ for 2 h. It was checked by UPLC until completion. The reaction mixture was purified by flash chromatography on silica gel (DCM: MeOH=60: 1) to give the product A15 as a white solid (2.3mg, 42%yield) .
Scheme 3. Synthesis of amine di-substituted compounds
Synthesis of compound 17
A flame-dried 50 mL round-bottom flask, concentrated sulfuric acid (15mL) , and 3-fluoro-2-chlorobenzaldehyde (12.6mmol, 2g, 1.0equiv) was added in small portions while stirring. Conc. nitric acid (4.0mL) was added dropwise at 0℃. The reaction mixture was stirred at 0 ℃ for 30min and then warmed to rt overnight. It was checked by TLC until completion. The reaction mixture was poured into 100mL ice water, the mixture was extracted with EA (3 x 50 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=300: 1) to give the pure compound 17 as a white solid (1.69g, 65.8%yield) .
Synthesis of compound 18
In a flame-dried 50 mL round-bottom flask, 3-fluoro-2-chloro-6-nitrobenzaldehyde (1.0g, 5.02mmol, 1.0equiv) was dissolved in methanol (20.0mL) . The reaction mixture was cooled to 0oC. NaBH4 (380mg, 10.05mmol, 2.0equiv) was added in small portions. The reaction mixture was stirred at 0 oC for 30min. TLC showed the starting material was consumed. The reaction mixture was quenched with ice water (50mL) , extracted with EA (3 x 50 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=15: 1) a to give compound 18 as a white solid (1.01g, 99%yield) .
Synthesis of compound 19
In a flame-dried 50 mL round-bottom flask, compound 18 (1.0g, 4.98mmol, 1.0equiv) was dissolved in dry DCM (11.0mL) , then dry Et
3N (1.04mL, 7.46mmol, 1.5equiv) was added. The mixture was cooled to 0℃. Methanesulfonyl chloride (0.46mL, 5.97mmol, 1.2equiv) was added in small portions. The reaction mixture was stirred at 0 ℃ for 30min. TLC showed the starting material was consumed. The reaction mixture was quenched with ice water (50mL) , extracted with EA (3 x 50 mL) , washed with Sat. NaHCO
3 and brine and then concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=10: 1) to give compound 19 as a white solid (1.21g, 87.2%yield) .
Synthesis of compound 20
In a flame-dried 50 mL round-bottom flask, compound 19 (200mg, 0.71mmol, 1.0equiv) , glycine ethyl ester hydrochloride (120mg, 0.86mmol, 1.2equiv) , were dissolved in dry DMF (5mL) , and then dry Et
3N (0.15mL, 1.07mmol, 1.5equiv, ) was added. The reaction mixture was stirred at 90℃ for 14h. TLC showed the starting material was consumed. The reaction mixture was quenched with ice water (50mL) , extracted with EA (3 x 50 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=10: 1) to give compound 20 as a white solid (158mg, 76.7%yield) .
Synthesis of compound 21
A flame-dried 10 mL round-bottom flask, compound 20 (30mg, 0.102mmol, 1.0equiv) , butan-1-amine (0.15mmol, 15μL, 1.5equiv) , and K
2CO
3 (0.3mmol, 41.4mg, 3.0equiv, ) were dissolved in dry DMF (1.0mL) . The reaction mixture was stirred at rt for 30min. TLC showed the starting material was consumed.. The reaction mixture was quenched with 5mL water, extracted with EA (3 x 10 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel (PE: EA=10: 1) and evaporated to give the pure compound 21 as a light yellow oil (30mg, 85.7%yield) .
Synthesis of compound 22
A flame-dried 100 mL 2-necked round-bottom flask, compound 21 (30mg, 0.09mmol, 1.0equiv) was dissolved in concentrated hydrochloric acid (1.0mL) . Stannous chloride (81mg, 0.438mmol, 5.0equiv) dissolved in hydrochloric acid (0.2mL) was added dropwise at rt. The reaction mixture was stirred at rt for 1h and checked by TLC until completion. The reaction mixture was poured into 5.0mL ice water (with 1.5 mL NH
3
. H
2O) , extracted with EA (3 x 10 mL) , washed with brine and concentrated. The mixture was purified by flash chromatography on silica gel(PE: EA=15: 1) and evaporated to give the pure compound 22 as a light yellow oil (15.2mg, 53.2%yield) .
Synthesis of compound 23
A flame-dried 50 mL 2-necked round-bottom flask, compound 22 (15.2mg, 0.048mmol, 1.0equiv) was dissolved in dry toluene (5.0mL) , and then cyanogen bromide (0.072mmol, 7.6mg, 1.5equiv) added in small portions while stirring at rt. The reaction mixture was stirred at 110 ℃ for 14h. It was checked by TLC until completion. The mixture was purified by flash chromatography on silica gel DCM/MeOH (10: 1) to get the compound 23 as a off-white solid (15mg, 92.4%yield) .
Synthesis of compound A23
A flame-dried 50 mL 2-necked round-bottom flask, compound 23 (15mg, 0.0443mmol, 1.0equiv) and triethylamine (0.066mmol, 9.2μL, 1.5equiv) were dissolved in ethanol (1.0mL) . T The reaction mixture was stirred at 100 oC for 14h. It was checked by TLC until completion. The reaction mixture was purified by flash chromatography on silica gel (DCM: MeOH=20: 1) to get the product A23 as a off-white solid (4.8mg, 37.3%yield) .
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.58 (s, 2H) , 6.86 (d, J=6.3 Hz, 1H) , 7.62 (d, 1H); HRMS (ESI) calculated for [M+H]
+ 299.9539, found 299.9531.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.52 (s, 2H) , 6.85 (dd, J=8.9Hz, 1H) , 7.27 (t, J= 9.0 Hz, 1H) , 11.13 (s, 1H) ; HRMS (ESI) calculated for [M+H]
+ 240.0340, found 240.0334.
1H NMR (400 MHz, MeOD+CDCl
3) : δ 3.61 (s, 2H) , 4.02 (s, 2H) , 5.34 (d, J=10.4 Hz, 1H) , 5.71 (d, J=17.4 Hz, 1H) , 6.92-6.87 (m, 1H) , 7.026.98 (m, 1H) , 7.51-7.50 (m, 1H) ; HRMS (ESI) calculated for [M+H]
+ 248.0591, found 248.0582.
1H NMR (400 MHz, MeOD+CDCl
3) : δ 4.02 (s, 2H) , 4.72 (s, 2H) , 6.98 (d, J=8.2 Hz, 1H) , 7.25 (d, J=8.2 Hz, , 1H) , 7.41-7.34 (m, 5H) ; HRMS (ESI) calculated for [M+H]
+ 298.0747, found 298.0739.
1H NMR (400 MHz, DMSO-d
6) : δ 3.88 (s, 2H) , 4.52 (s, 2H) , 7.08 (s, 1H) ; HRMS (ESI) calculated for [M+H]
+ 289.9655, found 289.9661.
1H NMR (400 MHz, DMSO-d
6) : δ 2.37 (s, 3H) , 3.87 (s, 2H) , 4.58 (s, 2H) , 6.96 (d, J=6.3 Hz, 1H) , 7.27-7.24 (m, 5H) ; HRMS (ESI) calculated for [M+H]
+ 312.0903, found 312.0894.
1H NMR (400 MHz, DMSO-d
6) : δ 3.74 (s, 2H) , 4.51 (s, 2H) , 6.86 (d, J=6.0 Hz, 1H) , 7.30-7.26 (m, 2H) , 7.60-7.58 (m, 2H) ; HRMS (ESI) calculated for [M+H]
+ 304.0311, found 304.0301.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.58 (s, 2H) , 6.83 (dd, J=1.9, 0.9 Hz, 1H) , 6.93 (d, J=6.3 Hz, 1H) , 7.43 (d, J=6.3 Hz, 1H) , 7.75 (t, J=1.7 Hz, 1H) , 8.05 (dd, J=1.6, 0.9 Hz, 1H); HRMS (ESI) calculated for [M+H]
+ 288.0539, found 288.0531.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.58 (s, 2H) , 6.97 (d, J=6.3 Hz, 1H) , 7.27 (d, J= 6.3 Hz, 1H) , 7.42-7.38 (m, 2H) , 7.52-7.48 (m, 2H) ; HRMS (ESI) calculated for [M+H]
+ 332.0357, found 332.0346.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.58 (s, 2H) , 6.98 (d, J=6.3 Hz, 1H) , 7.31 (d, J= 6.3 Hz, 1H) , 7.42 (dd, J=6.0, 2.7 Hz, 2H) , 8.63 (dd, J=6.0, 2.7 Hz, 2H) ; HRMS (ESI) calculated for [M+H]
+ 299.0696, found 299.0692.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.61 (s, 2H) , 7.00 (d, J=6.3 Hz, 1H) , 7.37 (d, J= 6.3 Hz, 1H) , 7.56-7.52 (m, 3H) , 7.97-7.91 (m, 4H) ; HRMS (ESI) calculated for [M+H]
+ 348.0903, found 348.0891.
1H NMR (400 MHz, DMSO-d
6) : δ 3.84 (s, 2H) , 4.57 (s, 2H) , 6.96 (d, J=6.3 Hz, 1H) , 7.28 (d, J= 6.3 Hz, 1H) , 7.60-7.58 (m, 2H) , 7.92-7.90 (m, 2H) ; HRMS (ESI) calculated for [M+H]
+ 323.0699, found 323.0690.
1H NMR (400 MHz, DMSO-d
6) : δ 3.86 (s, 2H) , 4.57 (s, 2H) , 6.81-6.79 (m, 2H) , 6.93 (d, J=6.3 Hz, 1H) , 7.21-7.16 (m, 3H) , 9.57 (s, 1H) ; HRMS (ESI) calculated for [M+H]
+ 314.0696, found 314.0687.
1H NMR (400 MHz, DMSO-d
6) : δ 3.84 (s, 2H) , 4.52 (s, 2H) , 6.89 (dd, J=8.0, 1.1 Hz, 1H) , 7.09 (dd, J=8.0, 1.1 Hz, 1H) , 7.23 (t, J=8.0 Hz, 1H) ; HRMS (ESI) calculated for [M+H]
+ 222.0434, found 222.0426.
1H NMR (400 MHz, DMSO-d
6) : δ 3.81 (s, 2H) , 4.48 (s, 2H) , 6.97 (s, 1H) , 7.22-7.19 (m, 2H) , 7.47-7.37 (m, 3H) ; HRMS (ESI) calculated for [M+H]
+ 332.0357, found 332.0346.
1H NMR (400 MHz, DMSO-d
6) : δ 3.65 (s, 2H) , 4.47 (s, 2H) , 6.83-6.80 (m, 1H) , 7.15-7.13 (m, 1H) , 7.21 (d, J=12 Hz, 2H) , 7.83 (d, J=8.0 Hz, 2H) ; HRMS (ESI) calculated for [M+H]
+ 342.0645, found 342.0636.
1H NMR (400 MHz, DMSO-d
6) : δ 3.90 (s, 2H) , 4.52 (s, 2H) , 7.05 (s, 1H) ; HRMS (ESI) calculated for [M+H]
+ 333.9149, found 333.9139.
1H NMR (400 MHz, DMSO-d
6) : δ 2.04 (s, 3H) , 3.87 (s, 2H) , 4.58 (d, J=4.8 Hz, 2H) , 6.97 (d, J= 6.3 Hz, 1H) , 7.07 (d, J=5.4 Hz, 1H) , 7.15 (d, J=6.3 Hz, 1H) , 7.26-7.21 (m, 1H) , 7.30-7.28 (m, 2H); HRMS (ESI) calculated for [M+H]
+ 312.0903, found 312.0894.
1H NMR (400 MHz, DMSO-d
6) : δ 2.34 (s, 3H) , 3.86 (s, 2H) , 4.58 (s, 2H) , 6.95 (d, J=6.0 Hz, 1H) , 7.19-7.15 (m, 3H) , 7.24 (d, J=6.0 Hz, 1H) , 7.34-7.30 (m, 1H) ; HRMS (ESI) calculated for [M+H]
+ 312.0903, found 312.0894.
1H NMR (400 MHz, DMSO-d
6) : δ 1.21 (t, J=5.4 Hz, 1H) , 2.64 (q, J=5.4 Hz, 2H) , 3.87 (s, 2H) , 4.58 (s, 2H) , 6.96 (d, J=6.3 Hz, 1H) , 7.28-7.24 (m, 3H) , 7.56-7.48 (m, 2H) ; HRMS (ESI) calculated for [M+H]
+ 326.1060, found 326.1051.
1H NMR (400 MHz, DMSO-d
6) : δ0.91 (t, J=5.4 Hz, 1H) , 1.61 (m, 2H) , 2.58 (t, J=5.7 Hz, 2H) , 3.87 (s, 2H) , 4.58 (s, 2H) , 6.96 (d, J=6.3 Hz, 1H) , 7.30-7.24 (m, 5H) ; HRMS (ESI) calculated for [M+H]
+ 340.1217, found 340.1207.
1H NMR (400 MHz, DMSO-d
6) : δ 1.22 (d, J=5.1 Hz, 6H) , 2.95-2.89 (m, 1H) , 3.87 (s, 2H) , 4.58 (s, 2H) , 6.96 (d, J=6.3 Hz, 1H) , 7.34-7.25 (m, 5H) , 11.16 (s, 1H) ; HRMS (ESI) calculated for [M+H]
+ 340.1217, found 340.1207.
1H NMR (400 MHz, DMSO-d
6) : δ0.89 (t, J=7.3 Hz, 3H) , 1.33 (m, 2H) , 1.52 (p, J=7.1 Hz, 2H) , 3.08 (q, J=6.7 Hz, 2H) , 3.80 (s, 2H) , 4.47 (s, 2H) , 5.06 (t, J=5.8 Hz, 1H) , 6.63 (d, J=8.8 Hz, 1H) , 6.79 (d, J=8.7 Hz, 1H) , 10.78 (s, 1H) ; HRMS (ESI) calculated for [M+H]
+ 293.1169, found 293.1175.
1H NMR (400 MHz, DMSO-d
6) : δ 3.79 (s, 2H) , 4.37 (d, J=6.2 Hz, 2H) , 4.48 (s, 2H) , 6.02 (t, J= 6.1 Hz, 1H) , 6.47 (d, J=8.7 Hz, 1H) , 6.67 (d, J=8.7 Hz, 1H) , 7.21-7.16 (m, 1H) , 7.32-7.26 (m, 4H) , 10.76 (s, 1H) ; HRMS (ESI) calculated for [M+H]
+ 327.1012, found 327.1003.
1H NMR (400 MHz, DMSO-d
6) : δ 1.56-1.42 (m, 4H) , 1.70-1.60 (m, 2H) , 1.98-1.88 (m, 2H) , 3.74 (q, J=6.4 Hz, 1H) , 3.80 (s, 2H) , 4.46 (s, 2H) , 4.69 (d, J=6.8 Hz, 1H) , 6.68 (d, J=8.8 Hz, 1H) , 6.80 (d, J=8.7 Hz, 1H) , 10.82 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 305.1169, found 305.1155.
1H NMR (400 MHz, DMSO-d
6) : δ 1.04 (t, J=7.0 Hz, 1H) , 1.39–1.11 (m, 3H) , 1.58 (d, J=12.4 Hz, 1H) , 1.71–1.64 (m, 2H) , 1.88 (d, J=11.9 Hz, 2H) , 3.28-3.22 (m, 1H) , 3.47–3.39 (m, 1H) , 3.80 (s, 2H) , . 4.46 (s, 2H) , 4.54 (d, J=8.4 Hz, 1H) , 6.70 (d, J=8.9 Hz, 1H) , 6.78 (d, J=8.8 Hz, 1H) , 10.81 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 319.1325, found 319.1312.
1H NMR (400 MHz, DMSO-d
6) : δ 1.90-1.80 (m, 4H) , 3.12-3.05 (m, 4H) , 3.83 (s, 2H) , 4.50 (s, 2H) , 6.82 (d, J=8.7 Hz, 1H) , 6.95 (d, J=8.7 Hz, 1H) , 11.02 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 291.1012, found 291.1017.
1H NMR (400 MHz, DMSO-d
6) : δ 1.54-1.47 (m, 2H) , 1.66-1.58 (m, 4H) , 2.81 (t, J=5.2 Hz, 4H) , 3.83 (s, 2H) , 4.50 (s, 2H) , 6.86 (d, J=8.6 Hz, 1H) , 7.05 (d, J=8.6 Hz, 1H) , 10.98 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 305.1169, found 305.1182.
1H NMR (400 MHz, DMSO-d
6) : δ 0.94 (d, J=6.4 Hz, 3H) , 1.35-1.19 (m, 2H) , 1.53-1.38 (m, 1H) , 1.72-1.63 (m, 2H) , 3.11-3.06 (m, 4H) , 3.84 (s, 2H) , 4.51 (s, 2H) , 6.87 (d, J=8.6 Hz, 1H) , 7.06 (d, J=8.6 Hz, 1H) , 8.91 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 319.1247, found 319.1241.
1H NMR (400 MHz, MeOD+DMSO-d
6) : δ 0.94 (d, J=6.4 Hz, 3H) , 1.36-1.20 (m, 2H) , 1.55-1.42 (m, 1H) , 1.74-1.63 (m, 2H) , 2.65–2.55 (m, 2H) , 3.17-3.11 (m, 2H) , 4.25 (s, 2H) , 4.64 (s, 2H) , 7.16 (s, 2H) , 9.84 (s, 2H) . HRMS (ESI) calculated for [M+H]
+ 355.1014, found [M-HCl+H]
+319.1241.
1H NMR (400 MHz, DMSO-d
6) : δ 2.34 (s, 3H) , 4.13 (s, 2H) , 4.66 (s, 2H) , 7.12 (d, J=8.5 Hz, 1H) , 7.26 (s, 4H) , 7.32 (d, J=8.3 Hz, 1H) . HRMS (ESI) calculated for [M+H]
+348.0670, found [M-HCl+H]
+ 312.0894.
δ, .
1H NMR (400 MHz, DMSO-d
6) : δ 1.55-1.46 (m, 2H) , 1.70-1.60 (m, 4H) , 2.85 (t, J=5.1 Hz, 4H) , 4.24 (s, 2H) , 4.64 (s, 2H) , 7.23-7.11 (m, 2H) , 9.99 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 341.0935, found [M-HCl+H]
+305.1182.
1H NMR (400 MHz, DMSO-d
6) : δ 3.38 (d, J=13.0 Hz, 2H) , 3.84 (s, 2H) , 4.53 (s, 2H) , 5.13-4.91 (m, 2H) , 5.89 (ddt, J=16.6, 10.1, 6.3 Hz, 1H) , 6.86 (d, J=8.2 Hz, 1H) , 7.18 (d, J=8.2 Hz, 1H) , 11.09 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 262.0747, found 262.0735.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.58 (s, 2H) , 6.96 (d, J=8.2 Hz, 1H) , 7.33-7.20 (m, 3H) , 7.45-7.36 (m, 2H) , 11.20 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 316.0652, found 316.0641.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.58 (s, 2H) , 6.98 (t, J=8.1 Hz, 1H) , 7.27 (d, J= 8.2 Hz, 1H) , 7.43-7.34 (m, 2H) , 7.57-7.45 (m, 2H) . HRMS (ESI) calculated for [M+H]
+ 332.0357, found 332.0348.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87 (s, 2H) , 4.59 (s, 2H) , 6.99 (d, J=8.3 Hz, 1H) , 7.31 (d, J= 8.2 Hz, 1H) , 7.66-7.55 (m, 2H) , 7.85-7.75 (m, 2 H) , 11.24 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 366.0621, found 366.0618.
1H NMR (400 MHz, DMSO-d
6) : δ 1.65-1.58 (m, 4H) , 1.76-1.66 (m, 4H) , 3.08-2.99 (m, 4H) , 3.81 (s, 2H) , 4.49 (s, 2H) , 6.82 (d, J=8.6 Hz, 1H) , 7.10 (d, J=8.6 Hz, 1H) , 10.94 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 319.1325, found 319.1320.
1H NMR (400 MHz, DMSO-d
6) : δ 1.66-1.58 (m, 4H) , 1.78-1.69 (m, 4H) , 3.13-3.06 (m, 4H) , 4.24 (s, 2H) , 4.62 (s, 2H) , 7.24-7.11 (m, 2H) . HRMS (ESI) calculated for [M+H]
+355.1092, found [M-HCl+H]
+ 319.1320.
1H NMR (400 MHz, DMSO-d
6) : δ 1.65-1.52 (m, 2H) , 1.93-1.83 (m, 2H) , 2.63 (t, J=11.4 Hz, 2H) , 3.14 (d, J=5.2 Hz, 1H) , 3.19 (d, J=11.6 Hz, 1H) , 3.82 (s, 2H) , 4.50 (s, 2H) , 6.86 (d, J=8.5 Hz, 1H) , 7.06 (d, J=8.4 Hz, 1H) , 10.98 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 373.1043, found 373.1035.
1H NMR (400 MHz, DMSO-d
6) : δ 1.59 (qd, J=12.4, 4.2 Hz, 2H) , 1.93-1.85 (m, 2H) , 2.75–2.58 (m, 2H) , 3.29-3.18 (m, 3H) , 4.24 (s, 2H) , 4.63 (s, 2H) , 7.23-7.14 (m, 2H) . HRMS (ESI) calculated for [M+H]
+ 409.0809, found [M-HCl+H]
+ 373.1036.
1H NMR (400 MHz, DMSO-d
6) : δ 2.41 (ddt, J=5.8, 3.7, 1.9 Hz, 2H) , 2.78 (dd, J=6.1, 5.3 Hz, 2H) , 3.25 (dq, J=4.4, 2.3 Hz, 2H) , 3.84 (s, 2H) , 4.52 (s, 2H) , 5.77 (tt, J=4.1, 1.8 Hz, 1H) , 6.87 (d, J=8.2 Hz, 1H) , 7.09 (d, J=8.2 Hz, 1H) , 11.14 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 320.0624, found 320.0619.
1H NMR (400 MHz, DMSO-d
6) : δ 2.25 (s, 3H) , 2.31 (dt, J=6.0, 3.3 Hz, 2H) , 2.52 (d, J=5.7 Hz, 2H) , 2.94 (q, J=2.9 Hz, 2H) , 3.83 (s, 2H) , 4.52 (s, 2H) , 5.63–5.56 (m, 1H) , 6.86 (d, J=8.2 Hz, 1H) , 7.09 (d, J=8.2 Hz, 1H) , 11.09 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 317.1169, found 317.1162.
1H NMR (400 MHz, DMSO-d
6) : δ 3.87-3.84 (m, 5H) , 4.56 (s, 2H) , 6.90 (d, J=8.3 Hz, 1H) , 7.42 (d, J=8.3 Hz, 1H) , 7.74 (d, J=0.8 Hz, 1H) , 8.07 (s, 1H) , 11.10 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 302.0808, found 302.0801.
1H NMR (400 MHz, DMSO-d
6) : δ 2.32 (d, J=0.8 Hz, 3H) , 3.87 (s, 2H) , 4.57 (s, 2H) , 6.23 (dt, J =3.3, 1.1 Hz, 1H) , 6.92–6.79 (m, 1H) , 6.95 (d, J=8.5 Hz, 1H) , 7.63 (d, J=8.5 Hz, 1H) , 11.22 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 302.0696, found 302.0687.
1H NMR (400 MHz, DMSO-d
6) : δ 1.52 (dt, J=12.7, 7.7 Hz, 4H) , 1.76 (t, J=7.0 Hz, 2H) , 3.07 (s, 2H) , 3.26 (d, J=7.0 Hz, 2H) , 3.55 (dq, J=11.9, 7.3 Hz, 4H) , 3.83 (s, 2H) , 4.49 (s, 2H) , 6.81 (d, J =8.7 Hz, 1H) , 6.95 (d, J=8.7 Hz, 1H) . HRMS (ESI) calculated for [M+H]
+ 361.1431, found 361.1425.
1H NMR (400 MHz, DMSO-d
6) : δ 1.85-1.73 (m, 2H) , 3.09-3.02 (m, 1H) , 3.56 (dd, J=9.9, 1.8 Hz, 1H) , 3.70 (dd, J=7.7, 1.8 Hz, 1H) , 3.81 (s, 2H) , 3.84 (d, J=7.7 Hz, 1H) , 4.26 (s, 1H) , 4.48 (s, 2H) , 4.52 (d, J=2.0 Hz, 1H) , 6.80 (d, J=8.7 Hz, 1H) , 6.93 (d, J=8.8 Hz, 1H) , 10.88 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 319.0962, found 319.0956.
1H NMR (400 MHz, DMSO-d
6) : δ 2.35 (t, J=0.7 Hz, 3H) , 3.87 (s, 2H) , 4.57 (s, 2H) , 6.97 (d, J= 8.3 Hz, 1H) , 7.14-7.05 (m, 2H) , 7.26-7.14 (m, 2H) , 11.21 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 330.0809, found 330.0801.
1H NMR (400 MHz, DMSO-d
6) : δ 2.26 (d, J=1.8 Hz, 3H) , 3.87 (s, 2H) , 4.57 (s, 2H) , 6.96 (d, J= 8.3 Hz, 1H) , 7.10 (dd, J=7.7, 1.8 Hz, 1H) , 7.15 (dd, J=10.8, 1.8 Hz, 1H) , 7.27 (d, J=8.2 Hz, 1H) , 7.38–7.30 (m, 1H) , 11.20 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 330.0809, found 330.0802.
1H NMR (400 MHz, CDCl
3+DMSO-d
6) : δ 1.97 (s, 3H) , 2.28 (s, 3H) , 3.97 (s, 2H) , 4.70-4.57 (m, 2H) , 6.89 (d, J=7.7 Hz, 1H) , 7.04–6.94 (m, 3H) , 7.08 (d, J=8.2 Hz, 1H) . HRMS (ESI) calculated for [M+H]
+ 326.1060, found 326.1049.
1H NMR (400 MHz, DMSO-d
6) : δ 1.96 (s, 3H) , 2.19 (s, 3H) , 2.22 (s, 3H) , 3.94 (s, 2H) , 4.67-4.54 (m, 2H) , 6.84 (s, 1H) , 7.00 (d, J=8.2 Hz, 1H) , 7.06 (s, 1H) , 7.14 (d, J=8.2 Hz, 1H) . HRMS (ESI) calculated for [M+H]
+ 340.1216, found 340.1207.
1H NMR (400 MHz, CDCl
3+CD
3OD) : δ 2.23 (s, 6H) , 4.02 (s, 2H) , 4.67 (s, 2H) , 7.03 (d, J=14.7 Hz, 3H) , 7.11 (d, J=7.6 Hz, 1H) , 7.19 (d, J=7.3 Hz, 1H) . HRMS (ESI) calculated for [M+H]
+ 326.1060, found 326.1049.
1H NMR (400 MHz, DMSO-d
6) : δ 2.38 (s, 3H) , 4.12 (s, 2H) , 4.65 (d, J=15.6 Hz, 2H) , 7.12 (d, J =8.2 Hz, 1H) , 7.28 (dd, J=7.8, 1.9 Hz, 1H) , 7.37 (d, J=8.3 Hz, 1H) , 7.48–7.41 (m, 2H) . HRMS (ESI) calculated for [M+H]
+ 346.0514, found 346.0502.
1H NMR (400 MHz, DMSO-d
6) : δ 2.05 (s, 3H) , 3.88 (s, 2H) , 4.65-4.52 (m, 2H) , 6.98 (d, J=8.2 Hz, 1H) , 7.14 (dd, J=18.5, 8.2 Hz, 1H) , 7.32 (dd, J=8.1, 2.4 Hz, 1H) , 7.42 (d, J=2.3 Hz, 1H) , 7.57–7.47 (m, 1H) , 11.28 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 346.0514, found 346.0502.
1H NMR (400 MHz, DMSO-d
6) : δ 3.18-3.14 (m, 4H) , 4.17 (s, 2H) , 4.67 (s, 2H) , 7.06 (q, J=1.3 Hz, 1H) , 7.15-7.13 (m, 3H) , 7.31 (dd, J=8.3, 2.3 Hz, 1H) . HRMS (ESI) calculated for [M+H]
+ 324.0903, found 324.0892.
1H NMR (400 MHz, DMSO-d
6) : δ 2.37 (s, 3H) , 3.89 (s, 2H) , 4.59 (s, 2H) , 6.98 (d, J=8.2 Hz, 1H) , 7.23 (ddd, J=19.3, 16.7, 8.3 Hz, 2H) , 7.37 (d, J=2.2 Hz, 1H) , 7.48 (d, J=8.3 Hz, 1H) , 11.13 (s, 1H) .
HRMS (ESI) calculated for [M+H]
+ 346.0514, found 346.0502.
1H NMR (400 MHz, DMSO-d
6) : δ 2.06 (s, 3H) , 3.86 (s, 2H) , 4.57 (s, 2H) , 4.90 (s, 2H) , 6.46-6.39 (m, 1H) , 6.58 (d, J=1.4 Hz, 1H) , 6.93 (d, J=14.7 Hz, 1H) , 6.93 (s, 1H) , 7.21-7.14 (m, 1H) . HRMS (ESI) calculated for [M+H]
+ 327.1012, found 327.1018.
1H NMR (400 MHz, DMSO-d
6) : δ 1.94 (dp, J=22.4, 7.4 Hz, 4H) , 2.71–2.57 (m, 2H) , 3.14 (t, J =8.5 Hz, 2H) , 3.85 (s, 2H) , 4.53 (s, 2H) , 6.08–6.00 (m, 1H) , 6.86 (d, J=8.3 Hz, 1H) , 7.21 (d, J =8.3 Hz, 1H) , 11.09 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 302.1060, found 302.1054.
1H NMR (400 MHz, DMSO-d
6) : δ 1.92 (q, J=7.8 Hz, 2H) , 2.42-2.37 (m, 2H) , 2.70-2.58 (m, 2H) , 3.81 (s, 2H) , 4.51 (s, 2H) , 6.02 (s, 1H) , 6.84 (d, J=8.4 Hz, 1H) , 7.19 (d, J=8.3 Hz, 1H) . HRMS (ESI) calculated for [M+H]
+ 288.0903, found 288.0892.
1H NMR (400 MHz, DMSO-d
6) : δ 1.86 (t, J=6.4 Hz, 2H) , 2.43-2.38 (m, 2H) , 2.49-2.44 (m, 2H) , 3.93 (s, 2H) , 4.01-3.98 (m, 4H) , 4.62 (s, 2H) , 5.60-5.56 (m, 1H) , 6.95 (d, J=8.2 Hz, 1H) , 7.17 (s, 1H) , 11.23 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 360.1115, found 360.1122.
1H NMR (400 MHz, DMSO-d
6) : δ0.97 (d, J=6.0 Hz, 3H) , 1.25-1.19 (m, 1H) , 1.73 (d, J=14.6 Hz, 3H) , 2.17 (d, J=17.0 Hz, 1H) , 2.30-2.21 (m, 2H) , 3.83 (s, 2H) , 4.51 (s, 2H) , 5.55 (s, 1H) , 6.84 (d, J=8.2 Hz, 1H) , 7.07 (d, J=8.2 Hz, 1H) , 11.10 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 316.1216, found 316.1225.
1H NMR (400 MHz, DMSO-d
6) : δ 3.88 (s, 2H) , 4.59 (s, 2H) , 7.09-6.93 (m, 2H) , 7.33-7.20 (m, 1H) , 7.52 (d, J=8.0 Hz, 2H) , 7.64 (d, J=8.0 Hz, 2H) , 11.23 (s, 1H) . HRMS (ESI) calculated for [M+H]
+ 348.0715, found 348.0708.
BIOLOGICAL ACTIVITY
We completed the synthesis of a large series of polycyclic agents and tested their activity of induce cell death. HeLa cells were treated with compounds A0-A61 for 48 h; wherein the A0 represented Anagrelide. Cell viability was determined by measuring ATP levels. Results were shown in table 1, figure 1 and figure 2.
Table 1. IC
50 of the Polycyclic agents on inducing HeLa cell death
Compound No. | IC50 a |
A0 (Anagrelide) | 6.668nM |
A1 | 2.533nM |
A2 | 34.19nM |
A3 | 10.4nM |
A4 | 0.563nM |
A5 | 0.6997nM |
A6 | 0.2963nM |
A7 | 1.772nM |
A8 | 0.5964nM |
A9 | 1.814nM |
A10 | 6.222nM |
A12 | 2.379nM |
A13 | 12.3nM |
A14 | 42.88nM |
A15 | 1.142nM |
A17 | 1.304nM |
A18 | 1.086nM |
A19 | 1.366nM |
A20 | 1.796nM |
A23 | 7.657nM |
A25 | 20.08nM |
A26 | >100μm |
A27 | 4.993nM |
A28 | 4.127nM |
A29 | 7.299nM |
A30 | 3.282nM |
A31 | 0.079nM |
A32 | 4.673nM |
A33 | 2.666nM |
A34 | 2.558nM |
A35 | 1.648nM |
A36 | 1.623nM |
A37 | 2.988nM |
A38 | 3.697nM |
A39 | 21.55nM |
A40 | 35.67nM |
A41 | 0.6374nM |
A42 | 12.83nM |
A43 | 12.19nM |
A44 | 0.5885nM |
A45 | 27.67nM |
A46 | 21.29nM |
A47 | 0.3013nM |
A48 | 0.1114nM |
A49 | 0.4051nM |
A50 | 5.979nM |
A51 | 1.021nM |
A52 | 6.772nM |
A53 | 0.7916nM |
A54 | 0.6122nM |
A55 | 0.6583nM |
A56 | 0.7833nM |
A57 | 0.2379nM |
A58 | 0.6316nM |
A59 | 28.02nM |
A60 | 0.5253nM |
A61 | 0.1726nM |
a. cell death assay on HeLa cells
Cell Survival Assay
Cell survival assay was performed using Cell Titer-Glo Luminescent Cell Viability Assay kit. A Cell Titer-Glo assay (Promega) was performed according to the manufacturer’s instructions. Luminescence was recorded with a Tecan GENios Pro plate reader.
RNA Degradation assay
HeLa (SLFN12
-/-) -3×Flag-HA-SLFN12 (wild type (WT) or K213R) cells were treated with DMSO, 10 nM A6 or co-treated with 10 nM and 25 nM Trequinsin at 37℃with 5%CO
2 for 24 h. Then cells were washed once with PBS and harvested by scraping and centrifugation at 800×g for 5 min. The harvested cells were washed with PBS and lysed for 30 min on ice in buffer containing 50 mM Tris-Hcl (pH 7.4) , 150mM Nacl, 1mM EDTA, 0.5%Triton X-100. The suspended lysate was cleared by centrifugation at 20,000 × g for 30 min. The 3×Flag-HA-SLFN12 (WT or K213R) protein or 3×Flag-HA-SLFN12 (WT or K213R) /PDE3A complex was purified by Flag M2 and HA beads and eluted by HA peptide. To study rRNA degradation assay, total RNA was extracted from HEK293T cells using RNA extraction kit (TIANGEN) following manufacturer’s protocol. Then 2.5 ug RNA was incubated with SLFN12 (WT or K213R) protein or SLFN12 (WT or K213R) /PDE3A complex at room temperature for 30 mins in the presence of ATP. After incubation, RNA was analyzed by electrophoresis.
HeLa xenograft models
HeLa, HeLa (PDE3A
-/-) , or HeLa (SLFN12
-/-) cells (5×10
6 per mouse) mixed with Matrigel (Corning) were subcutaneously injected into female nude mice (Balb/c-nude, 6–7 week) . Mice were maintained in an animal facility with 12 h light/12 h dark cycles, temperature (22–24℃) , humidity (40–60%) at the National Institute of Biological Sciences, Beijing. When the tumor volume reached about 60 mm
3, vehicle (10%DMSO, 30%PEG-4000, 60%Saline) , anagrelide (5 mg/kg) , A6 (1 mg/kg) and A6 (0.5 mg/kg) were intratumorally injected once per day for 22 days. Tumor volumes were calculated as (length×width
2) /2. Animal experiments were conducted following the Chinese Ministry of Health national guidelines and performed in accordance with institutional regulations reviewed and approved by the Institutional Animal Care and Use Committee of the National Institute of Biological Sciences.
Compound A6 shows better tumor growth inhibition than anagrelide
To evaluate the activity of compound A6 in vivo, we examined its effects on tumor growth in a mouse xenograft model. We firstly inoculated HeLa cells subcutaneously into female nude mice. The tumor-bearing mice were randomized into 4 groups (n=5/group) and received the following treatment via an oral gavage daily with methylcellulose: (a) vehicle; (b) anagrelide at 5 mg/kg; (c) compound A6 at 5mg/kg; and (d) compound A6 at 1mg/kg. The compound A6 (5mg/kg) treatment group showed the most dramatic tumor growth inhibition (Figure 3a, c, d) . For the anagrelide (5mg/kg) and compound A6 (1mg/kg) treatment groups, the tumor volume still increased with oral gavage once a day for 6 consecutive days. We subsequently treated the mice with oral gavage twice a day and the tumor volumes of anagrelide (5mg/kg) or compound A6 (1mg/kg) groups dramatically decreased compared with the untreated group. Notably, no bodyweight reduction was observed in all treatment groups (Figure 3b) .
Phosphodiesterase assay and LC–MS/MS analysis
A total of 10 ng purified PDE3A protein was incubated with 10μM cAMP (Sigma) in the presence of increasing concentrations of anagrelide and A1-A22 in the buffer used for the PDE assays at room temperature for 90 min. A tenfold excess of methanol was added to the reaction mixture, followed by centrifugation at 20,000×g for 10 min. The supernatant was then analyzed via LC–MS/MS.
LC–MS/MS analysis was performed using an Agilent 1290 Infinity UHPLC coupled to an Agilent 6495 Triple Quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode. The separation was carried out by a Waters ACQUITY UPLC BEH Amide column (2.1 mm×100 mm, 1.7μm) , heated at 35℃. The mobile phase consisted of water with 25 mM ammonium acetate and 25 mM ammonium hydroxide (A) and acetonitrile (B) with the following gradient: 0–1 min, 85%B; 1–12 min, 85–65%B; 12–12.1 min, 65–40%B; 12.1–15 min, 40%B; 15–15.1 min, 40–85%B; 15.1–20 min, 85%B. The flow rate was set at 0.3 mL/min. Overall, 1μl sample was injected. The MRM transitions were m/z 330.1→m/z 118.6 (CE 50V) and m/z 330.1→m/z 135.8 (CE 33V) in positive ionization mode. The concentration was calculated from external calibration curves constructed using a serial dilution of adenosine 3′, 5′-cyclic monophosphate solutions, ranging from 1 to 500 ng/mL. Data processing was performed with Agilent MassHunter software (Ver. B. 07.00) .
To anagrelide and A1-A61, the separation was carried out by a Agilent Zorbax Eclipse Plus C18 column (2.1 mm×50 mm, 1.8μm) , heated at 35℃. Mobile phase consisted of water with 0.1%formic acid (A) and acetonitrile with 0.1%formic acid (B) with the following gradient: 0–1 min, 5%B; 1–4 min, 5–95%B; 4–5 min, 95%B; 5–5.01 min, 95–5%B; 5.01–7 min, 5%B. The flow rate was set at 0.3 mL/min. Overall, 2μl sample was injected. The MRM transitions were m/z 288.12→273.1 (CE 39 V) and m/z 288.12→286.2 (CE 43V) in positive ionization mode.
Claims (23)
- A polycyclic compound having the following general formula (I) or formula (I’) , an optical isomer, a pharmaceutically acceptable salt, a prodrug, or a formulation thereof:Wherein,R 1, R 2, R 3, R 4, R 5, and R 6 are independently hydrogen, deuterium, hydrocarbon or heterohydrocarbon, heteroatom-containing functional group (non-hydrogen substituent) , halogen, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl, ; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;ring A is selected from optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S, optionally substituted C 1-C 10 alkylamino, optionally substituted C 6-C 10 arylamino, optionally substituted C 3-C 10 cycloalkylamino, optionally substituted-C 1-C 10 alkyl or heteroalkyl, optionally substituted-C 2-C 8 alkenyl or heteroalkenyl, optionally substituted-C 2-C 8 alkynyl or heteroalkynyl and optionally-C 1-C 10 substituted alkoxyl or heteroalkoxyl;group G is selected from CR 7R 8-, -C (O) -, -O-, -NR 9-, -S-and-S (O) 2-; R 7, R 8 and R 9 are independently selected from hydrogen, halogen, CN, optionally substituted-C 2-C 8 alkyl or heteroalkyl, optionally substituted-C 2-C 8 alkenyl or heteroalkenyl, optionally substituted-C 2-C 8 alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted -C 3-C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;group K is selected from CR 10R 11-, -C (O) -, -O-, -NR 12-, -S-and-S (O) 2-; n is 0, 1, 2, 3 or 4; R 10, R 11 and R 12 are independently selected from hydrogen, halogen, CN, optionally substituted -C 2-C 8 alkyl or heteroalkyl, optionally substituted-C 2-C 8 alkenyl or heteroalkenyl, optionally substituted-C 2-C 8 alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted-C 3-C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;X, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, -B-, -Se-, -S-, -CR 13R 14-, -NHR 15-, -NR 16R 17-, -O-, -C (O) -, -S (O) -and-S (O) 2-; and R 13, R 14, R 15, R 16 and R 17 at each occurrence are independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyls or heteroalkyl, alkenyl or heteroalkenyl, alkynyl or heteroalkynyl, aryl or heteroaryl, alkoxyl or heteroalkoxyl, including cyclic and substituted forms of each aryl and heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B and Se; and
- The compound according to claim 1, wherein the R 1, R 2, R 3, R 4, R 5, and R 6 are independently deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted (C1-C10) alkyl or (C1-C10) heteroalkyl, optionally substituted (C1-C10) aryl or (C1-C10) heteroaryl, optionally substituted (C2-C4) alkenyl or (C6-C8) alkenyl, optionally substituted (C2-C4) alkynyl or (C6-C8) alkynyl, (C1-C6) alkoxyl or (C6-C8) alkoxyl, 3-oxetanyloxy, 3-tetrahydrofuranyloxy, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl-SO 2-, (C3-C6) cycloalkyl, or a (C5-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S; orR 1, R 2, R 3, R 4, R 5, and R 6 are independently hydrogen, deuterium, halogen, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy, optionally substituted hydroxy, amino, optionally substituted amino, optionally substituted (C1-C6) alkyl, (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl, (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl-SO 2-, (C3-C6) cycloalkyl, or a (C5-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S; orR 1, R 2, R 3, R 4, R 5 and R 6 are independently hydrogen, deuterium, halogen, hydroxyl or optionally substituted hydroxy, optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl, or (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S; orR 1, R 2, R 3, R 4, R 5 and R 6 are independently hydrogen, deuterium, halogen, hydroxy, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, Si and S; orR 1, R 2, R 3, R 4, R 5 and R 6 are independently hydrogen, deuterium, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, Si and S; orR 1, R 2, R 3, R 4, R 5 and R 6 are all hydrogen.
- The compound according to claim 1, ring A is selected from optionally substituted 3-to 6-membered heterocycle and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orring A is selected from optionally substituted-C 5-C 6 cycloalkyl or heterocycle and optionally substituted 5-to 6-membered aryl or heteroaryl; wherein the heteroatom is selected from the group consisting of N, O and S; orring A is selected from optionally substituted 3-to 6-membered aryl or heteroaryl; wherein the heteroatom is selected from the group consisting of N, O and S; orring A is optionally substituted aryl or heteroaryl group derived from one of the following by removal of one hydrogen atom:wherein S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S; orring A is optionally substituted 6-membered aryl or heteroaryl group derived from one of the following by removal of one hydrogen atom:wherein S m are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, F, Cl, Br, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S; orring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, Cl, Br, F, CN, amino or optionally substituted amino, optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si and S; orring A is optionally substituted phenyl; wherein the optionally substituted groups are the same or different substituents and independently selected from hydrogen, deuterium, Cl, Br, F, CN, methyl, ethyl, vinyl and ethynyl; orring A is hydrophobic.
- The compound according to claim 1, wherein G is selected from CR 7R 8-, -C (O) -, -O-, -NR 9-, -S-and-S (O) 2-; R 7 and R 8 are same or different; R 7, R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 8 alkyl or heteroalkyl, optionally substituted-C 2-C 8 alkenyl or heteroalkenyl, optionally substituted-C 3-C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted 3-and 8-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; orG is selected from CR 7R 8-, -N-, =N-, -C (O) -, -O-and-NHR 9-; R 7 and R 8 are same or different; R 7, R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, CN, optionally substituted-C 2-C 6 alkyl or heteroalkyl, optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted-C 3-C 6 aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; orG is selected from CR 7R 8-, -N-, =N-and-NHR 9-; R 7 and R 8 are same or different; R 7, R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 6 alkyl or heteroalkyl, optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted-C 3-C 6 aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orG is selected from CR 7R 8-, =N-and-NR 9-; R 7 and R 8 are same or different; R 7, R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 6 alkyl, optionally substituted 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N and O; orG is selected from CR 7R 8-and-NR 9-; R 7 and R 8 are same or different; R 7, R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 3-C 6 alkyl or heteroalkyl, optionally substituted-C 3-C 6 cycloalkyl, or optionally substituted 5-to 6-membered heterocycle, optionally substituted-C 5-C 6 aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orG is selected from CR 7R 8-and-NR 9-; R 7 and R 8 are same or different; R 7, R 8 and R 9 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 8 alkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N and O; orG is selected from CR 7R 8-, -N-and=N-; R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 6 alkyl or heteroalkyl, optionally substituted -C 3-C 6 cycloalkyl, optionally substituted 6-membered heterocycle, optionally substituted-C 6 aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S; orG is CR 7R 8-; R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 6 alkyl or heteroalkyl, or optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P and S; orG is CR 7R 8-; R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orG is CR 7R 8-; R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orG is CR 7R 8-; R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen, optionally substituted 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orG is CR 7R 8-; R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium, halogen and optionally substituted phenyl; orG is CR 7R 8-; R 7 and R 8 are same or different, and independently selected from hydrogen, deuterium and halogen; orG is CR 7R 8-; R 7 and R 8 are different and independently selected from hydrogen, deuterium and halogen.
- The compound according to claim 1, wherein K is selected from CR 10R 11-, -C (O) -, -O-, -NR 12-, -S-and-S (O) 2-; n is 0, 1, 2, 3 or 4; R 10 and R 11 are same or different; R 10, R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 8 alkyl or heteroalkyl, optionally substituted-C 2-C 8 alkenyl or heteroalkenyl, optionally substituted-C 3-C 8 cycloalkyl, optionally substituted 3-to 8-membered heterocycle, optionally substituted 3-and 8-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si Se, and S; orK is selected from CR 10R 11-, -N-, =N-, -C (O) -, -O-and-NHR 12-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10, R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, CN, optionally substituted-C 2-C 6 alkyl or heteroalkyl, optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted-C 3-C 6aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; orK is selected from CR 10R 11-, -N-, =N-and-NHR 12-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10, R 11 and R 12 independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 6 alkyl or heteroalkyl, optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted-C 3-C 6 aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orK is selected from CR 10R 11-, =N-and-NR 12-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10, R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 6 alkyl, optionally substituted 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N and O; orK is selected from CR 10R 11-and-NR 12-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10, R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, optionally substituted -C 2-C 8 alkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N and O; orK is selected from CR 10R 11-and-NR 12-; n is 1 or 2; R 10 and R 11 are same or different; R 10, R 11 and R 12 are independently selected from hydrogen, deuterium, halogen, optionally substituted -C 3-C 6 alkyl or heteroalkyl, optionally substituted-C 3-C 6 cycloalkyl, or optionally substituted 5-to 6-membered heterocycle, optionally substituted-C 5-C 6 aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orK is selected from CR 10R 11-, -N-and=N-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from hydrogen, deuterium, halogen, optionally substituted -C 2-C 6 alkyl or heteroalkyl, optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 6-membered heterocycle, optionally substituted-C 6 aryl or heteroaryl, wherein the heteroatom is selected from the group consisting of N, O and S; orK is CR 10R 11-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from hydrogen, deuterium, halogen, optionally substituted-C 2-C 6 alkyl or heteroalkyl, or optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P and S; orK is CR 10R 11-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from hydrogen, deuterium, halogen, optionally substituted 3-to 6-membered heterocycle, optionally substituted 3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orK is CR 10R 11-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from optionally hydrogen, deuterium, halogen, substituted-3-to 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orK is CR 10R 11-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from hydrogen, deuterium, halogen, optionally substituted 6-membered aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O and S; orK is CR 10R 11-; n is 1, 2 or 3; R 10 and R 11 are same or different; R 10 and R 11 are independently selected from hydrogen, deuterium, halogen and optionally substituted phenyl; orK is CR 10R 11-; n is 1, 2 or 3; R 10 and R 11 are same or different, and independently selected from hydrogen, deuterium and halogen; orK is CR 10R 11-; n is 1, 2 or 3; R 10 and R 11 are different and independently selected from hydrogen, deuterium and halogen.
- The compound according to claim 1, wherein B is selected from optionally substituted -C 1-C 6 alkyl or heteroalkyl, optionally substituted-C 2-C 6 alkenyl or heteroalkenyl, optionally substituted-C 2-C 6 alkynyl or heteroalkynyl and optionally-C 1-C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle; orB is selected from optionally substituted-C 1-C 2 alkyl or heteroalkyl, optionally substituted –C 2-C 3 alkenyl or heteroalkenyl, optionally substituted–C 2-C 3 alkynyl or heteroalkynyl and optionally-C 1-C 2 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle; orB is selected from optionally substituted–C 3-C 4 alkyl or heteroalkyl, optionally substituted –C 5-C 6 alkyl or heteroalkyl, optionally substituted–C 4-C 6 alkenyl or heteroalkenyl, optionally substituted –C 4-C 6 alkynyl or heteroalkynyl, optionally –C 3-C 4 substituted alkoxyl or heteroalkoxyl and optionally–C 5-C 6 substituted alkoxyl or heteroalkoxyl; preferably, the optional substitutes are same or different and independently selected from heteroatom-containing functional group (non-hydrogen substituent) , hydroxy or optionally substituted hydroxy, halogen, CN, amino or optionally substituted amino, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle; orB is optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S; preferably, the optional substitutes are same or different and independently selected from optionally substituted (C3-C6) aryl, (C3-C6) heteroaryl, (C3-C6) cycloalkyl and (C3-C6) heterocycle; orB is F; G is CR 7R 8-, wherein R 7 and R 8 are different and independently selected from hydrogen and halogen (F, Cl or Br) ; and K is CR 10R 11-, wherein R 9 and R 10 are same or different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3; orB is Cl; G is CR 7R 8-, wherein R 7 and R 8 are different and independently selected from hydrogen and halogen (F, Cl or Br) ; and K is CR 10R 11-, wherein R 9 and R 10 are different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3; orB is Br; G is CR 7R 8-, wherein R 7 and R 8 are different and independently selected from hydrogen and halogen (F, Cl or Br) ; and K is CR 10R 11-, wherein R 9 and R 10 are same or different and independently selected from hydrogen, deuterium and halogen (F, Cl or Br) , n is 1, 2 or 3.
- The compound according to any claims of 1, 5 or 6, wherein n is 1; orn is 2 and K represent the same group or different groups.
- The compound according to claim 1, wherein X, Y, Z, W, and Q are each independently selected from the group consisting of-N-, =O-, =S, -B-, -S-, -CR 13R 14-, -NHR 15-, -NR 16R 17-, -O-, -C (O) -, -S (O) -and-S (O) 2-; and R 13, R 14, R 15, R 16 and R 17 at each occurrence are independently selected from the group consisting of hydrogen, halogen, optionally substituted (C1-C6) alkyl, optionally substituted (C3-C6) aryl, optionally substituted (C3-C6) cycloalkyl and a (C5-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, B, Si, P and S; orX,Y, Z, W and Q are each independently selected from the group consisting of-N-, =O, =S, -B-, -S-, -CR 13R 14-, -NHR 15-, -NR 16R 17-, -O-, -C (O) -, -S (O) -and-S (O) 2-; and R 13, R 14, R 15, R 16 and R 17 at each occurrence are independently selected from optionally substituted (C1-C6) alkyl or (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl or (C3-C6) heteroaryl, optionally substituted (C2-C4) alkenyl, optionally substituted (C2-C4) alkynyl, (C1-C6) alkoxyl, fluoro-substituted (C1-C2) alkyl, (C1-C6) alkyl -SO 2-, (C3-C6) cycloalkyl, or (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, P, B, Si, Se and S; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O, =S, -S-, -CR 13R 14-, -NHR 15-, -NR 16R 17-, -O-, -C (O) -, -S (O) -and-S (O) 2-; and R 13, R 14, R 15, R 16 and R 17 at each occurrence are independently selected from optionally substituted (C1-C6) alkyl, (C1-C6) heteroalkyl, optionally substituted (C3-C6) aryl, (C3-C6) heteroaryl, optionally substituted (C3-C6) cycloalkyl and (C3-C6) heterocycle having 1 or 2 heteroatoms each independently selected from the group consisting of N, O, B, Si and S; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, =N-, -O-, -C (O) -, -S (O) -and-S (O) 2-; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, =N-, -S-, -O-, -C (O) -, -S (O) -and-S (O) 2-; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, -B-, -S-, -O-, -C (O) -, -S (O) -and-S (O) 2-; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-, -O-, =S and-S-; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =S, =N-, -O-and-S-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:wherein R 3, R 4, R 5 and R 6 are independently defined as above; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:wherein R 3, R 4, R 5, and R 6 are independently defined as above; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:wherein R 3, R 4, R 5, and R 6 are independently defined as above; orX, Y, Z, W and Q are each independently selected from the group consisting of-N-, =O-, =N-and-O-, and the combination of these atoms to form optionally substituted aryl or heteroaryl ring, optionally substituted cycloalkyl or heterocycle that are derived from one of the following by removal of one hydrogen atom:wherein R 5, and R 6 are independently defined as above; orX, Y, Z, W and Q are combined with other atoms to form optionally substituted cycloalkyl, or heterocycle that are derived from one of the following by removal of one hydrogen atom:wherein R 3, and R 4 are independently defined as above.
- The compound according to any of claims 1-8, wherein the compound has the following general formula (II) or formula (II’) :wherein,R a, R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, CN, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; and
- The compound according to any of claims 1-8, wherein the compound has the following general formula (III) or formula (III’) :wherein,R a, R b and R c are independently selected from hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl, wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S; and
- The compound according to any of claims 1-11, wherein the compound has the following general (IV) or formula (IV’) :Wherein R 1, R 2, R 3, R 4, and R 5 are independently hydrogen, deuterium, hydrocarbon or heterohydrocarbon, heteroatom-containing functional group (non-hydrogen substituent) , halogen, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl, ; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;R a, R b, and R c, are independently hydrogen, deuterium, hydrocarbyl or heterohydrocarbyl, heteroatom-containing functional group (non-hydrogen substituent) , halogen, hydroxy or optionally substituted hydroxy, amino or optionally substituted amino, optionally substituted alkyl or heteroalkyl, optionally substituted alkenyl or heteroalkenyl, optionally substituted alkynyl or heteroalkynyl, optionally substituted alkoxyl or heteroalkoxyl, optionally substituted ring or heterocycle, optionally substituted aryl or heteroaryl, ; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;ring A is selected from optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, P, B, Si, Se and S;B is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, P, B, Si, Se and S, optionally substituted C 1-C 10 alkylamino, optionally substituted C 6-C 10 arylamino, optionally substituted C 3-C 10 cycloalkylamino, optionally substituted-C 1-C 10 alkyl or heteroalkyl, optionally substituted-C 2-C 8 alkenyl or heteroalkenyl, optionally substituted-C 2-C 8 alkynyl or heteroalkynyl and optionally-C 1-C 10 substituted alkoxyl or heteroalkoxyl.
- The compound of claim 12, wherein R 1, R 2, R 3, R 4, and R 5 are independently hydrogen, deuterium, C 1-C 6 alkyl, C 6-C 10 aryl, C 3-C 10 heteroaryl; R a is fluorine, chlorine, bromine, or iodine, R b and R c are independently hydrogen, deuterium, fluorine, chlorine, bromine, iodine, C 1-C 6 alkyl, C 6-C 10 aryl, or C 3-C 10 heteroaryl; and/orring A is selected from optionally substituted-C 3-C 6 cycloalkyl, optionally substituted 3-to 6-membered heterocycle, optionally substituted 7 to 12-membered heterocycle, and optionally substituted 3-to 6-membered aryl or heteroaryl; wherein hetero-form comprises 1-6 heteroatoms selected from the group consisting of N, O, and S; and/orB is selected from halogen, optionally substituted heteroatom selected from the group consisting of N, O, and S, optionally substituted C 1-C 10 alkylamino, optionally substituted C 6-C 10 arylamino, optionally substituted C 3-C 10 cycloalkylamino, optionally substituted-C 1-C 10 alkyl or heteroalkyl, optionally substituted-C 2-C 8 alkenyl or heteroalkenyl, optionally substituted-C 2-C 8 alkynyl or heteroalkynyl and optionally-C 1-C 10 substituted alkoxyl or heteroalkoxyl.
- A pharmaceutical composition containing the compound, a pharmaceutically acceptable salt, prodrug or a formulation thereof according to any of claims 1-15, and at least one of pharmaceutically acceptable diluents, excipients and carriers;preferably, the pharmaceutical composition or formulation is in a form suitable for oral, topical, transdermal, injection, rectal or inhalation administration, especially in the form of tablets, capsules, solutions, liquids, gels, ointments, syrup, spray, nebulizer or suppositories;preferably, the carrier is selected from one or more of phosal 50 propylene glycol (PG) , polyethylene glycol (PEG) 400, PEG300, DMSO, ethanol, and Tween 80.
- Use of the compound, a pharmaceutically acceptable salt, prodrug, or a formulation thereof according to any of claims 1-15 or the pharmaceutical composition according to claim 16 as PDE3A modulator and/or SLFN12 modulator;preferably, the modulator is capable of inhibiting, disrupting and/or accelerating the activity of PDE3A and/or the activity of SLFN12.
- Use of the compound, a pharmaceutically acceptable salt, prodrug, or a formulation thereof according to any of claims 1-15 or the pharmaceutical composition according to claim 16 as a reagent regulating PDE3A and SLFN12 interaction;preferably, the reagent is capable of enhancing and/or promoting the interaction of PDE3A and SLFN12.
- Use of the compound, a pharmaceutically acceptable salt, prodrug, or a formulation thereof according to any of claims 1-15 or the pharmaceutical composition according to claim 16 for the manufacture of a medicament to treat or prevent a disease or disorder associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12.
- Use of the compound, a pharmaceutically acceptable salt, prodrug, or a formulation thereof according to any of claims 1-15 or the pharmaceutical composition according to claim 16 for the treatment or prevention of a disease or disorder of cancer or tumor;preferably, for treatment or inhibition of caner and/or inhibition of growth of cancer cells;preferably, the cancer or tumor is associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12,preferably, the cancer or tumor is selected from Leukemia, lymphoma, myelodysplastic syndrome or myeloma, preferably selected from acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute T-cell leukemia, acute lymphoblastic leukaemia (all) , chronic lymphoblastic leukemia (CLL) , acute monocytic leukemia (amol) , mantle cell lymphoma (MCL) , B-cell lymphoma Histiocytic lymphoma or multiple myeloma,preferably, the cancer or tumor is selected from: adenocarcinoma, squamous cell carcinoma, adenosarcoma, undifferentiated carcinoma, large cell carcinoma or small cell carcinoma, hepatocellular carcinoma, hepatoblastoma, colon adenocarcinoma, renal cell carcinoma, renal cell adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, glioblastoma, glioma, head and neck cancer, lung cancer, breast cancer, Merkel cell carcinoma, rhabdomyosarcoma, malignant melanoma, Epidermoid carcinoma, lung cancer, renal cancer, adenocarcinoma of the breast, breast cancer, breast cancer, breast cancer, non-small cell lung cancer, ovarian cancer, oral cancer, anal cancer, skin cancer, Ewing's sarcoma, gastric cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Villum's tumor, Walden West Len's globulinemia, pancreatic cancer, pancreatic adenocarcinoma, cervical cancer, squamous cell carcinoma, medulloblastoma, prostate cancer, Malignant tumor or metastatic induced secondary tumor of colon cancer, colon adenocarcinoma, transitional cell carcinoma, osteosarcoma, ductal carcinoma, large cell lung cancer, small cell lung cancer, ovarian adenocarcinoma, ovarian teratoma, bladder papilloma, neuroblastoma, glioblastoma multiforme, glioblastoma, astrocytoma, epithelioid carcinoma, melanoma or retinoblastoma.
- A method for preventing or treating a disease or disorder associated with PDE3A, SLFN12 and/or the interaction of PDE3A and SLFN12, comprising administering to a subject in need thereof the compound, a pharmaceutically acceptable salt, prodrug, or a formulation thereof according to any of claims 1-15 or the pharmaceutical composition according to claim 16.
- A method for preventing or treating a disease or disorder of cancer or tumor, comprising administering to a subject in need thereof the compound, a pharmaceutically acceptable salt, prodrug, or a formulation thereof according to any of claims 1-15 or the pharmaceutical composition according to claim 16;preferably, the cancer or tumor is selected from Leukemia, lymphoma, myelodysplastic syndrome or myeloma, preferably selected from acute myeloid leukemia (AML) , chronic myeloid leukemia (CML) , acute T-cell leukemia, acute lymphoblastic leukaemia (all) , chronic lymphoblastic leukemia (CLL) , acute monocytic leukemia (amol) , mantle cell lymphoma (MCL) , B-cell lymphoma Histiocytic lymphoma or multiple myeloma,preferably, the cancer or tumor is selected from: adenocarcinoma, squamous cell carcinoma, adenosarcoma, undifferentiated carcinoma, large cell carcinoma or small cell carcinoma, hepatocellular carcinoma, hepatoblastoma, colon adenocarcinoma, renal cell carcinoma, renal cell adenocarcinoma, colorectal cancer, colorectal adenocarcinoma, glioblastoma, glioma, head and neck cancer, lung cancer, breast cancer, Merkel cell carcinoma, rhabdomyosarcoma, malignant melanoma, Epidermoid carcinoma, lung cancer, renal cancer, adenocarcinoma of the breast, breast cancer, breast cancer, breast cancer, non-small cell lung cancer, ovarian cancer, oral cancer, anal cancer, skin cancer, Ewing's sarcoma, gastric cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Villum's tumor, Walden West Len's globulinemia, pancreatic cancer, pancreatic adenocarcinoma, cervical cancer, squamous cell carcinoma, medulloblastoma, prostate cancer, Malignant tumor or metastatic induced secondary tumor of colon cancer, colon adenocarcinoma, transitional cell carcinoma, osteosarcoma, ductal carcinoma, large cell lung cancer, small cell lung cancer, ovarian adenocarcinoma, ovarian teratoma, bladder papilloma, neuroblastoma, glioblastoma multiforme, glioblastoma, astrocytoma, epithelioid carcinoma, melanoma or retinoblastoma.
- The method according to claim 21 or 22, wherein the method is monotherapy or combination therapy.
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