WO2024120471A1 - Composés ciblant un mutant de p53 - Google Patents

Composés ciblant un mutant de p53 Download PDF

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WO2024120471A1
WO2024120471A1 PCT/CN2023/136981 CN2023136981W WO2024120471A1 WO 2024120471 A1 WO2024120471 A1 WO 2024120471A1 CN 2023136981 W CN2023136981 W CN 2023136981W WO 2024120471 A1 WO2024120471 A1 WO 2024120471A1
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membered
alkyl
heterocycloalkyl
cycloalkyl
amino
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PCT/CN2023/136981
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English (en)
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Sujing LI
Amin LI
Qian Zheng
Chaojie DANG
Xinrui FAN
Wei LONG
Yanping Wang
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Jacobio Pharmaceuticals Co., Ltd.
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Publication of WO2024120471A1 publication Critical patent/WO2024120471A1/fr

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  • the present invention relates to compounds targeting p53 mutants, pharmaceutical compositions comprising the compounds, methods of preparing the compounds and methods of using the compounds to prevent or treat a disease or condition related to p53 mutants.
  • the p53 protein referred to as the “guardian of the human genome” is a tetrameric transcription factor that prevents mutation to the genome by regulating the expression of a subgroup of target genes. Although biologically active as a homotetramer, each p53 monomer is comprised of 393 amino acids, and is divided into five key regulatory domains: the transactivation domain (TAD) , proline-rich region (PR) , the DNA binding domain (DBD) , the oligomerization domain (OD) , and the C-terminus.
  • TAD transactivation domain
  • PR proline-rich region
  • DBD DNA binding domain
  • OD oligomerization domain
  • C-terminus the C-terminus
  • the p53 protein Under normal conditions, the p53 protein has a “cancer suppressor” effect but p53 is unstable, with a half-life ranging from 5 to 30 minutes. Activation of p53 initiates pathways involved in apoptosis, DNA repair, cell cycle arrest, anti-angiogenesis, and senescence in order to avoid propagation of damaged cells. p53 activation occurs via a complicated regulatory network composed of three key steps: (1) p53 stabilization by phosphorylation, (2) DNA binding, and (3) target gene activation.
  • mutant p53 is the most frequently mutated protein in human cancer. As examples, mutations are present in 96%of ovarian serous carcinomas, 87%of metastatic gastric cancers, 85%of small cell lung cancers, and 75%of pancreatic cancers, and are also associated with worsened prognosis and patient survival. Further, mutant p53 is a highly abundant and tumour-specific target as it is typically overexpressed in cancer, partly as a result of its inability to induce MDM2 gene expression in order to establish a negative feedback loop to control p53 expression. As a result of its overexpression, mutant p53 also possesses toxic GoF properties that can propagate and cause malfunctions to other important proteins and pathways that regulate the cell cycle.
  • mutant p53 represents an important pharmacological target and the past two decades have seen considerable dedication to the development of small molecules that aim to restore wild-type function in mutant p53.
  • targeting mutant p53 means to more selectively target the cancer cells, reducing the risk of side effects and toxicity towards healthy tissues.
  • numerous mechanistic strategies have been developed including protein refolding via cysteine modification, protein stabilization, modulation of protein aggregation, and zinc chelation.
  • P53 is inactivated directly by mutation in 50%of human cancers (ranging from about 1%to 85%depending on the type of cancer) , and almost all cancers exhibit malfunction along the p53 pathway.
  • the frequency and aggressive nature of cancers exhibiting p53 malfunction has driven a widespread effort both in academia and the pharmaceutical industry to restore normal p53 expression and activity over the past decades. While this approach is faced with significant challenges including frequent off-target mechanisms of action, major technological advancements in gene sequencing capability and a shift towards personalized medicine holds significant promise for the development of small molecules capable of mutant-specific p53 reactivation.
  • Mutations in p53 located in the DNA binding domain of the protein or periphery of the DNA-binding surface result in aberrant protein folding required for DNA recognition and binding. Mutations in p53 can occur, for example, at amino acids Val143, His168, Arg175, Tyr220, Gly245, Arg248, Arg249, Phe270, Arg273, and Arg282.
  • P53 mutations that can abrogate the activity of p53 include, for example, R175H, Y220C, G245S, R248Q, R248W, R273H, and R282W. These p53 mutations can either distort the structure of the DNA-binding site or thermodynamically destabilize the folded protein at body temperature. Wild-type function of p53 mutants can be recovered by binding of the p53 mutant to a compound that can shift the folding-unfolding equilibrium towards the folded state, thereby reducing the rate of unfolding and destabilization.
  • the p53 Y220C mutation is associated with many cancers, e.g., breast cancer, non-small cell lung cancer, colorectal cancer, pancreatic cancer, and ovarian cancer.
  • PC14586 was reported to be a small molecule reactivator targeting p53 Y220C mutant developed by PMV Pharmaceuticals, Inc., there is still a critical need in the art for the development of new small molecule reactivators targeting p53 mutants (e.g., Y220C mutant) with high specificity and activity as well as low toxicity.
  • it is an object of the present invention to provide a pharmaceutical composition comprising the above-mentioned compound targeting mutant p53.
  • the present disclosure further provides the following aspect.
  • a compound of formula (I) or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof:
  • one of X 1 , X 2 , X 3 and X 4 is selected from N or CR 2 , and the others of X 1 , X 2 , X 3 and X 4 are each independently selected from N or CR 4 ;
  • X 5 is selected from N or CR 1 ;
  • E is selected from alkylene, alkenylene or alkynylene
  • R 1 is independently selected from hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, -OR’ , -SR’ , -C (O) R’ , -C (O) N (R’ ) 2 , -C (O) OR’ , -OC (O) R’ , -OC (O) N (R’ ) 2 , -N (R’ ) 2 , -NR’ C (O) R’ , -NR’ C (O) OR’ , -NR’ C (O) N (R’ ) 2 , -S (O) R’ , -S (O) N (R’ ) 2 , -NR’S (O) R’ , -NR’S (O) N (R’ ) 2 , -NR’S (O) R’ , -
  • R 2 is -NR 51 R 52 , -OR 53 or -SR 54 ;
  • R 3 is selected from hydrogen, deuterium, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C (O) R’ , -C (O) N (R’ ) 2 , -C (O) OR’ , -S (O) R’ , -S (O) N (R’ ) 2 , -S (O) 2 R’ , -S (O) 2 N (R’ ) 2 , -PO (R’ ) 2 , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl; said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C
  • each R 3a is independently selected from deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR’ , -SR’ , -C (O) R’ , -C (O) N (R’ ) 2 , -C (O) OR’ , -OC (O) R’ , -OC (O) N (R’ ) 2 , -N (R’ ) 2 , -NR’ C (O) R’ , -NR’ C (O) OR’ , -NR’ C (O) N (R’ ) 2 , -S (O) R’ , -S (O) N (R’ ) 2 , -NR’S (O) R’ , -NR’S (O) N (R’ ) 2 , -NR’S (O) R
  • each R 3b is independently selected from deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, oxo, -OR’ , -SR’ , -C (O) R’ , -C (O) N (R’ ) 2 , -C (O) OR’ , -OC (O) R’ , -OC (O) N (R’ ) 2 , -N (R’ ) 2 , -NR’ C (O) R’ , -NR’ C (O) OR’ , -NR’ C (O) N (R’ ) 2 , -S (O) R’ , -S (O) N (R’ ) 2 , -NR’S (O) R’ , -NR’S (O) N (R’ ) 2 , -NR’S (O) R
  • R 4 at each occurrence is independently selected from hydrogen, deuterium, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, -OR’ , -SR’ , -C (O) R’ , -C (O) N (R’ ) 2 , -C (O) OR’ , -OC (O) R’ , -OC (O) N (R’ ) 2 , -N (R’ ) 2 , -NR’ C (O) R’ , -NR’ C (O) OR’ , -NR’ C (O) N (R’ ) 2 , -S (O) R’ , -S (O) N (R’ ) 2 , -NR’S (O) R’ , -NR’S (O) N (R’ ) 2 , -NR’S (O) R’
  • R 51 , R 52 , R 53 and R 54 are each independently selected from hydrogen, deuterium, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C (O) R’ , -C (O) N (R’ ) 2 , -C (O) OR’ , -S (O) R’ , -S (O) N (R’ ) 2 , -S (O) 2 R’ , -S (O) 2 N (R’ ) 2 , -PO (R’ ) 2 , 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-12 membered aryl, 5-12 membered heteroaryl, or -C 1-6 alkyl-C 3-12 heterocycloalkyl; said
  • R 11 and R 12 are independently selected from hydrogen, deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkyl, -C 1-6 haloalkyl, -C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 or 3-6 membered cycloalkyl; wherein said -C 1-6 alkyl, -C 1-6 alkoxy and 3-6 membered cycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkoxy, -NH-C 1-6 alkyl, -N (C 1-4 alkyl) 2 , or 3-6 membered cycloalkyl; or
  • R 11 or R 12 and R 3 together with atoms to which they are respectively attached form a ring, such as, monocyclic, bicyclic, or polycyclic 3-12 membered alicyclic group, 3-12 membered heterocyclyl, 6-12 membered aryl, or 5-12 membered heteroaryl, which ring is independently optionally substituted with one or more R 3a ;
  • R 13 is selected from hydrogen, deuterium, -C 1-6 alkyl or 3-6 membered cycloalkyl; wherein said -C 1-6 alkyl and 3-6 membered cycloalkyl are each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from deuterium, -OH, halogen, -CN, oxo, -C 1-6 alkoxy, -NH 2 , -NHC 1-6 alkyl, or -N (C 1-4 alkyl) 2 ; or
  • R 3 and R 13 together with the nitogen atom to which they are attached form a ring, such as, monocyclic, bicyclic, or polycyclic 3-12 membered alicyclic group, 3-12 membered heterocyclyl, 6-12 membered aryl, or 5-12 membered heteroaryl, which ring is independently optionally substituted with one or more R 3a ;
  • each R’ at each occurrence is independently selected from hydrogen, deuterium, halogen, -OH, -CN, oxo, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , -C 1-6 alkyl, -C 1-6 alkylOC 1-6 alkyl, -C 1-6 alkyl-NHC 1-6 alkyl, -C 1-6 alkyl-N (C 1-6 alkyl) 2 , -C 1-6 haloalkyl, -OC 1-6 alkyl, -C (O) OC 1-6 alkyl, -C 3-14 cycloalkyl, -C 3-14 heterocycloalkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, 6-12 membered aryl, or 5-12 membered heteroaryl; wherein said -C 1-6 alkyl, -OC 1-6 alkyl, -C 3-14 cyclo
  • heterocycloalkyl, heterocycloalkenyl, and heteroaryl each independently contains 1, 2, 3, 4, 5 or 6 heteroatoms selected from N, O, P or S;
  • n is selected from 1, 2, 3, 4, 5 or 6.
  • X 2 , X 3 , and X 4 in the formula (I-1) are each independently selected from N or CR 4 ;
  • X 2 is independently selected from N or CR 4 .
  • R 1 is independently selected from halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl, said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 6-10 membered aryl, and 5-12 membered heteroaryl are independently optionally
  • R 1 is independently selected from -F, -Cl, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, -CN, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, 5-12 membered heteroaryl, said -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkynyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, 6-10 membered aryl, and 5-12 membered heteroaryl are independently optionally substituted with one or more (such as 1, 2, 3, 4, 5 or 6) substituents selected from -F, -Cl, -OH, -C 1-3 alkyl, -C 2-4 alkenyl, -C 2-4 alkyn
  • R 1 is independently selected from -F, -Cl, -C 1-3 alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 5 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S, or 6 membered heteroaryl containing 1 or 2 heteroatoms selected from N; said -C 1-3 alkyl, -C 1-3 haloalkyl, 3-6 membered cycloalkyl, 5 membered heteroaryl and 6 membered heteroaryl are each independently optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -OH, -C 1-3 alkyl, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N (C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl.
  • R 1 is independently selected from -C 1-3 alkyl, -C 1-3 haloalkyl, or 5 membered heteroaryl containing 1 or 2 heteroatoms selected from N, O or S; and R 1 is optionally substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -OH, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N (C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl.
  • R 51 is selected from -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -C (O) R’ , -C (O) N (R’ ) 2 , -C (O) OR’ , 3-6 membered cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl or -C 1-6 alkyl-C 3-12 heterocycloalkyl; said -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, 3-6 membered cycloalkyl, 3-10 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl and -C 3-12 heterocycloalkyl are each independently optionally substituted with one
  • R 51 is selected from 8 membered bridged heterocyclyl, -C (O) -C 3-5 heterocycloalkyl, or -C 1-3 alkyl-C 3-5 heterocycloalkyl, said 8 membered bridged heterocyclyl, -C 1-3 alkyl or -C 3-5 heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6 R 5e ;
  • R 5a , R 5c and R 5d are each independently selected from hydrogen; -C 1-6 alkyl; or -C 1-6 alkyl substituted with 1, 2, 3, 4, 5 or 6 substituents selected from -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N (C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl;
  • R 5b and R 5e are each independently selected from -F, -C 1-6 alkyl, oxo, -OC 1-6 alkyl, -NH 2 , -NHC 1-6 alkyl, -N (C 1-6 alkyl) 2 , -CN or 3-6 membered cycloalkyl, wherein, said -C 1-6 alkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from -F, -C 1-3 alkyl, oxo, -OC 1-3 alkyl, -NH 2 , -NHC 1-3 alkyl, -N (C 1-3 alkyl) 2 , -CN or 3-6 membered cycloalkyl.
  • R 3 is independently selected from 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl; said 3-12 membered heterocycloalkenyl, 6-10 membered aryl, or 5-12 membered heteroaryl at each occurrence is independently optionally substituted with one or more R 3a substituents selected from halogen, NH 2 , NH-C 1-6 alkyl, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 haloalkyl, -CN, -NO 2 , -OR’ , -SR’ , -C (O) R’ , oxo, -C (O) N (R’ ) 2 , -C (O) OR’ , -OC (O) R’ , -N (R’ ) 2 , -NR’ C
  • R 11 or R 12 is hydrogen or oxo; or R 11 or R 12 and R 3 together with atoms to which they are respectively attached form 5-12 membered heterocyclyl, preferably indolinyl, optionally substituted with one or more R 3a .
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) , or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof according to any one of items 1-22, and a pharmaceutically acceptable carrier, diluent, or excipient.
  • a compound of formula (I) or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof according to any one of items 1-22, or a pharmaceutical composition according to item 23 for use in the prevention or treatment of a disease or condition related to p53 mutant protein in a subject.
  • a method for preventing or treating a disease or condition related to p53 mutant protein in a subject comprising administering to a subject a therapeutically effective amount of a compound of formula (I) , or a stereoisomer, tautomer, deuterated derivative, prodrug or pharmaceutically acceptable salt thereof according to any one of items 1-22, or a pharmaceutical composition according to item 23.
  • the present invention provides compounds, compositions and methods for restoring wild-type function of mutant p53.
  • the compounds of the present invention can bind to mutant p53 and restore the ability of the p53 mutant to bind DNA.
  • the restoration of activity of the p53 mutant can allow for the activation of downstream effectors of p53 leading to inhibition of cancer progression.
  • the present invention further provides a method for treating a disease or condition related to p53 mutant protein. There is also provided a method for preparation of a compound of the present invention.
  • the compounds of the present invention can selectively bind to a p53 mutant and can recover wild-type activity of the p53 mutant including, for example, DNA binding function and activation of downstream targets involved in tumor suppression.
  • a compound of the invention selectively binds to the p53 Y220C mutant.
  • the Y220C mutant is a temperature sensitive mutant, which binds to DNA at lower temperature and is denatured at body temperature.
  • a compound of the invention can selectively bind to the p53 Y220Cs and stabilize the Y220C mutant to reduce the likelihood of denaturation of the protein at body temperature.
  • assays can be utilized to detect, for example, a conformational change in the p53 mutant or activation of wild-type p53 targets.
  • Conformational changes in p53 can be measured by, for example, differential scanning fluorimetry (DSF) , isothermal titration calorimetry (ITC) , nuclear magnetic resonance spectrometry (NMR) , or X-ray crystallography.
  • DFS differential scanning fluorimetry
  • ITC isothermal titration calorimetry
  • NMR nuclear magnetic resonance spectrometry
  • antibodies specific for the wild type of mutant conformation of p53 can be used to detect a conformational change via, for example, immunoprecipitation (IP) , immunofluorescence (IF) , or immunoblotting.
  • IP immunoprecipitation
  • IF immunofluorescence
  • Methods used to detect the ability of the p53 mutant to bind DNA can include, for example, DNA affinity immunoblotting, modified enzyme-linked immunosorbent assay (ELISA) , electrophoretic mobility shift assay (EMSA) , fluorescence resonance energy transfer (FRET) , homogeneous time-resolved fluorescence (HTRF) , and a chromatin immunoprecipitation (ChIP) assay.
  • DNA affinity immunoblotting DNA affinity immunoblotting
  • ELISA modified enzyme-linked immunosorbent assay
  • EMSA electrophoretic mobility shift assay
  • FRET fluorescence resonance energy transfer
  • HTRF homogeneous time-resolved fluorescence
  • ChIP chromatin immunoprecipitation
  • Activation of p53 effector proteins can be detected by, for example, immunohistochemistry (IHC-P) , reverse transcription polymerase chain reaction (RT-PCR) , and western blotting.
  • IHC-P immunohistochemistry
  • RT-PCR reverse transcription polymerase chain reaction
  • the activation of p53 can also be measured by the induction of apoptosis via the caspase cascade and using methods including, for example, Annexin V staining, TUNEL assays, pro-caspase and caspase levels, and cytochrome c levels.
  • Another consequence of p53 activation is senescence, which can be measured using methods such as ⁇ -galactosidase staining.
  • the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising” in that these latter terms are “open” transitional terms that do not limit claims only to the recited elements succeeding these transitional terms.
  • C 1-6 alkyl refers to an alkyl group as defined hereinafter having 1 to 6 carbon atoms in total
  • C 3-8 cycloalkyl refers to a cycloalkyl group as defined hereinafter having 3 to 8 carbon atoms in total
  • C 6-10 aryl refers to an aryl group as defined hereinafter having 6 to 10 carbon atoms in total.
  • Carbon atoms that may exist in the substituents of the chemical group are not included in the total number of carbon atoms in the shorthand notation.
  • arylalkyl means that the aryl group is attached to the rest of the molecule via the alkyl group
  • alkoxyl means that the aliphatic group is attached to the rest of the molecule via an oxy group
  • alkyl optionally substituted by one or more means the alkyl group is unsubstituted or substituted by one or more (such as 1, 2, 3, 4, 5 or 6) halogens, and that the description includes both substituted alkyl groups and unsubstituted alkyl groups.
  • substituted means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom's normal valence is not exceeded.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra-or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the phrase "optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures. All the stereoisomers of the invention can be identified and determined by conventional X-ray single crystal diffraction analysis. The present invention contemplates various stereoisomers and mixtures thereof.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center (s) .
  • the pre fixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory.
  • these stereoisomers are identical except that they are mirror images of one another.
  • a spec ific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiom eric mixture.
  • a 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur w here there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • the terms “racemic mix ture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer refers to an isomer resulted from a proton shift from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compound of formula (I) of the present invention are included within the scope of the present invention.
  • structures depicted herein are also meant to include all isomeric forms of the structure, e.g., racemic mixtures, cis/trans isomers, geometric (or conformational) isomers, such as (Z) and (E) isomers.
  • geometric (or conformational) isomers such as (Z) and (E) isomers.
  • the compound having a double bond or cycle in the present application includes both E-and Z-geometric isomers.
  • isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention and their uses.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 32 P, 33 P, 35 S, 18 F, 36 Cl, 123 I or 125 I.
  • isotopes of hydrogen include deuterium and tritium.
  • the isotopes of hydrogen can be denoted as 1 H (hydrogen) , 2 H (deuterium) and 3 H (tritium) . They are also commonly denoted as D for deuterium and T for tritium.
  • CD 3 denotes a methyl group wherein all of the hydrogen atoms are deuterium.
  • Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the present disclosure are equivalent to those unlabeled, for example, deuterated compounds of the present disclosure are equivalent to those non-deuterated.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.
  • deuterated derivative refers to a compound having the same chemical structure as a reference compound, but with one or more hydrogen atoms replaced by a deuterium atom ( “D” or “ 2 H” ) . It will be recognized that some variation of natural isotopic abundance occurs in a synthesized compound depending on the origin of chemical materials used in the synthesis. Notwithstanding this variation, the concentration of naturally abundant stable hydrogen isotopes is small and immaterial as compared to the degree of stable isotopic substitution of deuterated derivatives described herein.
  • the deuterated derivatives disclosed herein have an isotopic enrichment factor for each deuterium atom, of at least 3500 (52.5%deuterium incorporation at each designated deuterium) , at least 4500 (67.5%deuterium incorporation at each designated deuterium) , at least 5000 (75%deuterium incorporation at each designated deuterium) , at least 5500 (82.5%deuterium incorporation at each designated deuterium) , at least 6000 (90%deuterium incorporation at each designated deuterium) , at least 6333.3 (95%deuterium incorporation at each designated deuterium) , at least 6466.7 (97%deuterium incorporation at each designated deuterium) , or at least 6600 (99%deuterium incorporation at
  • amino refers to the -NH 2 group.
  • cyano refers to the -CN group.
  • nitro refers to the -NO 2 group.
  • halogen as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo.
  • the preferred halogen groups include -F, -Cl and -Br.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched.
  • alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl.
  • C 1-6 as in C 1-6 alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.
  • alkenyl means a straight or branch-chained hydrocarbon radical containing one or more (such as 1, 2, 3, 4, 5 or 6) double bonds and typically from 2 to 20 carbon atoms in length.
  • C 2-6 alkenyl contains from 2 to 6 carbon atoms.
  • Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.
  • alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more (such as 1, 2, 3, 4, 5 or 6) triple bonds and typically from 2 to 20 carbon atoms in length.
  • C 2-6 alkynyl contains from 2 to 6 carbon atoms.
  • Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.
  • alkoxyl radicals are oxygen ethers formed from the previously described alkyl groups.
  • a “cycloalkyl” is a cyclic hydrocarbon which is completely saturated. “cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl has from 3 to about 12 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined, examplary “cycloalkyl” groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings.
  • spirocyclic cycloalkyl refers to a bicyclic cycloalkyl in which each of the rings shares one adjacent atom with the other ring.
  • fused cycloalkyl refers to a bicyclic cycloalkyl in which each of the rings shares two adjacent atoms with the other ring.
  • bridged cycloalkyl refers to a cycloalkyl that includes at least two bridgehead carbon atoms and at least one bridging carbon atom.
  • bridged cycloalkyl includes “bicyclic bridged cycloalkyls” which includes two bridgehead carbon atoms and “polycyclic bridged cycloalkyls” which includes more than two bridgehead carbon atoms.
  • Typical bridged cycloalkyls include, but are not limited to adamantyl, noradamantyl, bicyclo [1.1.0] butanyl, norboranyl (bicyclo [2.2.1] heptanyl) , norbornenyl (bicyclo [2.2. l] heptanyl) , norbornadienyl (bicyclo [2.2.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group containing 1 to 4 rings and 3 to 8 carbons per ring system. Exemplary such groups include cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. “cycloalkenyl” includes monocyclic, bicyclic, tricyclic, or tetracyclic ring system in which one, two, three or more atoms are shared between the two rings. The term “spirocyclic cycloalkenyl” refers to a bicyclic cycloalkenyl in which each of the rings shares one adjacent atom with the other ring.
  • fused cycloalkenyl refers to a polycyclic cycloalkenyl in which two rings shares two adjacent atoms.
  • bridged cycloalkenyl refers to a cycloalkenyl that includes at least two bridgehead atoms and at least one bridging atom. “bridged cycloalkenyl” includes “bicyclic bridged cycloalkenyl” which includes two bridgehead atoms and “polycyclic bridged cycloalkenyl” which includes more than two bridgehead atoms.
  • heterocycloalkyl refers to a stable 3-18 membered non-aromatic ring radical completely saturated that comprises two to twelve carbon atoms and from one to six heteroatoms selected from such as nitrogen, oxygen, phosphorus and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system.
  • spirocyclic heterocycloalkyl or “spiro-heterocyclyl” refers to a polycyclic heterocycloalkyl in which two rings shares one atom.
  • fused heterocycloalkyl refers to a polycyclic heterocycloalkyl in which two rings shares two adjacent atoms.
  • bridged heterocycloalkyl or “bridged-heterocyclyl” refers to a heterocycloalkyl that includes at least two bridgehead atoms and at least one bridging atom.
  • Bridged heterocycloalkyl or “bridged-heterocyclyl” includes “bicyclic bridged heterocycloalkyl” which includes two bridgehead atoms and “polycyclic bridged heterocycloalkyl” which includes at least two bridgehead atoms.
  • the heteroatoms in the heterocycloalkyl radical are optionally oxidized.
  • the heterocycloalkyl is attached to the rest of the molecule through any atom of the ring (s) .
  • heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl [1, 3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl octahydroisoindoly, 2-oxopiperazinyl, 2-oxopiperidiny1, 2-oxopyrrolidinyl, oxazolidinyl, piperidnyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, te
  • heterocycloalkenyl refers to the above-mentioned hererocycloalkyl having at least one double bond.
  • a heterocycloalkenyl may be a single ring or multiple rings wherein the multiple rings include “spirocyclic heterocycloalkenyl” , “fused heterocycloalkenyl” , and “bridged heterocycloalkenyl” .
  • “Spirocyclic heterocycloalkenyl” refer to a polycyclic heterocycloalkenyl in which two rings shares one atom
  • “fused heterocycloalkenyl” refers to a polycyclic heterocycloalkenyl in which two rings shares two adjacent atoms
  • “bridged heterocycloalkyl” refers to a heterocycloalkenyl that includes at least two bridgehead atoms and at least one bridging atom.
  • “Bridged heterocycloalkenyl” includes “bicyclic bridged heterocycloalkenyl” which includes two bridgehead atoms and “polycyclic bridged heterocycloalkenyl” which includes more than two bridgehead atoms.
  • aryl refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are mono cyclic or bicyclic aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • heteroaryl represents an aromatic ring system containing carbon (s) and at least one heteroatom.
  • Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted.
  • a monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms.
  • a polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bicyclic heteroaryl is a polycyclic heteroaryl.
  • Bicyclic heteroaryl rings may contain from 8 to 12 ring atoms.
  • Monocyclic heteroaryl rings may contain from 5 to 8 ring atoms (cabons and heteroatoms) .
  • heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adeninyl, quinolinyl or isoquinolinyl.
  • heterocyclyl or “heterocycle” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (e.g., at least one annular heteroatom selected from oxygen, nitrogen, phosphorus and sulfur) .
  • a heterocyclyl group has from 3 to about 20 annular atoms, for example from 3 to 12 annular atoms, for example from 3 to 10 annular atoms, for example from 5 to 10 annular atoms or for example from 5 to 6 annular atoms.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the rings of the multiple condensed ring (e.g. bicyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • heterocyclyl or “heterocyclic ring” or “heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond) .
  • a heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro.
  • heterocyclyl has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclyl) , 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclyl) , 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclyl) , 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclyl) , 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclyl) , 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclyl) , or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocyclyl) ; having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms,
  • heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl.
  • bridged-heterocyclyl refers to a four-to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four-to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur.
  • bridged-heterocyclyl includes bicyclic and tricyclic ring systems.
  • spiro-heterocyclyl refers to a ring system in which a three-to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three-to ten-membered cycloalkyl or three-to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three-to ten-membered heterocyclyl.
  • spiro-heterocyclyl examples include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro [3.5] nonanyl, 2-oxa-6-azaspiro [3.4] octanyl, and 6-oxa-1-azaspiro [3.3] heptanyl.
  • Heterocyclyl groups also include partially unsaturated ring systems containing one or more double bonds, including fused ring systems with one aromatic ring and one non-aromatic ring, but not fully aromatic ring systems. Examples include dihydroquinolines (e.g. 3, 4-dihydroquinoline) , dihydroisoquinolines (e.g.
  • heterocycles include 3, 8-diazabicyclo [3.2.1] octanyl, 2, 5-diazabicyclo [2.2.1] heptanyl, 3, 6-diazabicyclo [3.1.1] heptanyl, 3-oxa-7, 9-diazabicyclo [3.3.1] nonanyl, and hexahydropyrazino [2, 1-c] [1, 4] oxazinyl, for example.
  • the terms “heterocycle” , “heterocyclyl” , and “heterocyclic ring” are used interchangeably.
  • any hydrogen atom bonded with C, N, O, or S in the 3-12 membered cycloalkyl, 3-12 membered cycloalkenyl, 3-12 membered heterocycloalkyl, 3-12 membered heterocycloalkenyl, 3-12 membered heterocyclyl, 6-10 membered aryl or 5-12 membered heteroaryl can be replaced with the substituent.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.
  • the present invention includes any possible solvates and polymorphic forms.
  • a type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable.
  • water, ethanol, propanol, acetone or the like can be used.
  • the compounds of this disclosure are capable of forming acid addition salt and/or base addition salt by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • pharmaceutically acceptable salt of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di (substituted alkyl) amines, tri (substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di (substituted alkenyl) amines, tri (substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, etc.
  • primary, secondary and tertiary amines such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di (substituted alkyl) amines, tri
  • Suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri (iso-propyl) amine, tri (n-propyl) amine, ethanolamine, 2-dime thylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Salts derived from organic acids include salts of acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like. Since the compounds are intended for pharmaceutical use, they are preferably provided in substantially pure form, for example at least 60%pure, more suitably at least 75%pure, especially at least 98%pure (%are on a weight for weight basis) .
  • prodrug refers to a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.
  • the term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants.
  • the compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • the compounds or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous) .
  • the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient.
  • compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion.
  • the compound or a pharmaceutically acceptable salt thereof may also be administered by controlled release means and/or delivery devices.
  • the compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more (such as 1, 2, 3, 4, 5 or 6) necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.
  • compositions of this invention may include a pharmaceutically acceptable carrier and the above-mentioned compound or a pharmaceutically acceptable salt thereof.
  • the compounds or pharmaceutically acceptable salts thereof can also be included in pharmaceutical compositions in combination with one or more (such as 1, 2, 3, 4, 5 or 6) other therapeutically active compounds.
  • a tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more (such as 1, 2, 3, 4, 5 or 6) accessory ingredients or adjuvants.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • Each tablet preferably contains from about 0.05mg to about 5g of the active ingredient and each cachet or capsule preferably containing from about 0.05mg to about 5g of the active ingredient.
  • a formulation intended for the oral administration to humans may contain from about 0.5mg to about 5g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition.
  • Unit dosage forms will generally contain between from about 0.0lmg to about 2g of the active ingredient, typically 0.01mg, 0.02mg, 1mg, 2mg, 3mg, 4mg, 5mg, 6mg, 7mg, 8mg, 9mg, 10mg, 25mg, 50mg, l00mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or l000mg.
  • compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • the final injectable form must be sterile and must be effectively fluid for easy syringability.
  • the pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol) , vegetable oils, and suitable mixtures thereof.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05wt%to about 10wt%of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first mixing the composition with the softened or melted carrier (s) followed by chilling and shaping in molds.
  • the pharmaceutical formulations described above may include, as appropriate, one or more (such as 1, 2, 3, 4, 5 or 6) additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like.
  • other adjuvants can be included to render the formulation isotonic with the blood of
  • dosage levels on the order of from about 0.001mg/kg to about 150mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05mg to about 7g per patient per day.
  • inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS) may be effectively treated by the administration of from about 0.001 to 50mg of the compound per kilogram of body weight per day or alternatively about 0.05mg to about 3.5g per patient per day.
  • a method of treating a cancer comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of the invention.
  • a compound of the invention can, for example, slow the proliferation of cancer cell lines, or kill cancer cells.
  • Non-limiting examples of cancer that can be treated by a compound of the invention include: acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related cancers, AIDS-related lymphoma, anal cancer, bladder cancer, bone cancers, brain tumors, such as cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, central nervous system lymphoma, cerebellar astrocytoma, cervical cancer, colon cancer, gallbladder cancer, gastric cancer, head and neck cancer, heart cancer, hepatocellular (liver) cancer, kidney cancer, liver cancer, lung cancers, such as non-small cell and small cell lung cancer, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, pancreatic cancer,
  • Step 1 2, 2-trifluoro-1- (7-nitrobenzo [b] thiophen-3-yl) ethan-1-one.
  • Step 2 7-nitro-3- (perfluoroethyl) benzo [b] thiophene.
  • Step 6 (Z) -3-fluoro-N- (2-iodo-3- (perfluoroethyl) benzo [b] thiophen-7-yl) piperidin-4-amine (racemic) .
  • Step 7 (Z) -3-fluoro-N- (2-iodo-3- (perfluoroethyl) benzo [b] thiophen-7-yl) -1-methylpiperidin-4-amine (racemic) .
  • Step 8 (4- ( (3- (7- ( ( (Z) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (perfluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (racemic) (1) .
  • the reaction mixture was stirred at 50 °C for 3 h.
  • the eluate was concentrated under vacuum.
  • the resulting crude product was further purified by pre-HPLC with ACN/H 2 O (0.1%ammonium hydroxide) , Flow rate: 70 mL/min; Gradient: 30-70-95%B (2-30-33min) ; 245 nm; RT: 37.76-39.52.
  • Step 3 dimethyl (7- (prop-2-yn-1-ylamino) benzofuran-4-yl) phosphine oxide.
  • Step 4 (7- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) benzofuran-4-yl) dimethylphosphine oxide (2) .
  • the reaction mixture was stirred at 50 °C for 3 h.
  • the eluate was concentrated under vacuum.
  • the resulting crude product was further purified by pre-HPLC with ACN/H 2 O (0.1%ammonium hydroxide) , Flow rate: 70 mL/min; Gradient: 35-68-71%B (2-30-33min) ; 268 nm; RT: 30.35-32.77.
  • Step 1 4-bromo-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) aniline.
  • Step 2 (4-amino-3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl) phenyl) dimethylphosphine oxide.
  • Step 3 (4-amino-3- (1H-pyrazol-5-yl) phenyl) dimethylphosphine oxide.
  • Step 4 dimethyl (4- (prop-2-yn-1-ylamino) -3- (1H-pyrazol-5-yl) phenyl) phosphine oxide.
  • Step 5 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3- (1H-pyrazol-3-yl) phenyl) dimethylphosphine oxide (3) .
  • the reaction mixture was stirred at 50 °C for 3 h.
  • the eluate was concentrated under vacuum.
  • the resulting crude product was further purified by prep-HPLC with ACN/H 2 O (0.1%ammonium hydroxide) , Flow rate: 70 mL/min; Gradient: 35-67-67%B (2-30-33min) ; 268 nm; RT: 29.55-31.48.
  • Step 4 3- (bromomethyl) -7-chlorothieno [2, 3-c] pyridine.
  • Step 5 7-chloro-3- (2, 2, 2-trifluoroethyl) thieno [2, 3-c] pyridine.
  • Step 6 7-chloro-2-iodo-3- (2, 2, 2-trifluoroethyl) thieno [2, 3-c] pyridine.
  • Step 8 (3-methoxy-4- ( (3- (7- ( (1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) thieno [2, 3-c] pyridin-2-yl) prop-2-yn-1-yl) amino) phenyl) dimethylphosphine oxide (4) .
  • the reaction mixture was stirred at 50 °C for 3 h.
  • the eluate was concentrated under vacuum.
  • the resul ting crude product was further purified by prep-HPLC with MeOH/H 2 O (0.1%ammonium hydroxide) , Flow rate: 70 mL/min; Gradient: 35-64-85%B (2-28-46min) ; 260 nm; RT: 35.32-39.48.
  • Step 2 tert-butyl (2-methoxy-4-nitrophenyl) (prop-2-yn-1-yl) carbamate.
  • Step 3 tert-butyl (4-amino-2-methoxyphenyl) (prop-2-yn-1-yl) carbamate.
  • Step 4 ethyl (4- ( (tert-butoxycarbonyl) (prop-2-yn-1-yl) amino) -3-methoxyphenyl) glycinate.
  • Step 5 tert-butyl (chlorosulfonyl) carbamate.
  • Step 6 ethyl N- (4- ( (tert-butoxycarbonyl) (prop-2-yn-1-yl) amino) -3-methoxyphenyl) -N- (N- (tert-butoxycarbonyl) sulfamoyl) glycinate.
  • Step 7 ethyl N- (3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) -N-sulfamoylglycinate.
  • Step 8 5- (3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide.
  • Step 9 5- (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen -2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) -1, 2, 5-thiadiazolidin-3-one-1, 1-dioxide (5) .
  • the reaction mixture was stirred at 50 °C for 3 h.
  • the eluate was concentr ated under vacuum.
  • the resulting crude product was further purified by pre-HPLC with ACN/H 2 O (0.1%a mmonium hydroxide) , Flow rate: 70 mL/min; Gradient: 30-70-90%B (2-30-35min) ; 265 nm; RT: 29.50-31.48.
  • Step 1 4- ( (2-iodo-3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) amino) tetrahydro-2H-thiopyran-1-oxide.
  • the resulting solution was cooled to room temp erature and added to water (50 mL) .
  • the resulting solution was extracted with EA (2 x 50 mL) .
  • the organic layers were combined and washed with brine (30 mL) , dried over anhydrous Na 2 SO 4 , concentrated under vacuum.
  • Step 3 tert-butyl (1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl) (2-iodo-3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) carbamate.
  • Step 4 tert-butyl (2- (3- ( (4- (dimethylphosphoryl) -2-methoxyphenyl) amino) prop-1-yn-1-yl) -3- (2, 2, 2-trifluoro ethyl) benzo [b] thiophen-7-yl) (1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl) carbamate.
  • Step 5 (4- ( (3- (7- ( (1-imino-1-oxidohexahydro-1l6-thiopyran-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (6) .
  • the resulting crude product was further purified by pre-HPLC with ACN/H 2 O (0.05%ammonium hydroxide) , Flow rate: 70 mL/min; Gradient: 35-70-70%B (2-30-60min) ; 266 nm; RT: 19.43-20.51.
  • Step 1 (1S, 3S, 4R) -4- ( (2- (3- ( (4- (dimethylphosphoryl) -2-methoxyphenyl) amino) prop-1-yn-1-yl) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) amino) -3-fluoro-1-methylpiperidine-1-oxide (10) and (1R, 3S, 4R) -4- ( (2- (3- ( (4- (dimethylphosphoryl) -2-methoxyphenyl) amino) prop-1-yn-1-yl) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) amino) -3-fluoro-1-methylpiperidine-1-oxide (7) .
  • Step 1 (1S, 3S, 4R) -3-fluoro-4- ( (2- (3- ( (2-methoxy-4- ( (R) -S-methylsulfonimidoyl) phenyl) amino) prop-1-yn-1-yl) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) amino) -1-methylpiperidine-1-oxide (8) and (1R, 3S, 4R) -3-fluo ro-4- ( (2- (3- ( (2-methoxy-4- ( (R) -S-methylsulfonimidoyl) phenyl) amino) prop-1-yn-1-yl) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) amino) -1-methylpiperidine-1-oxide (9) .
  • the resulting solution was added to saturated Na 2 CO 3 (aq. ) (30 mL) .
  • the resulting solution was extracted with DCM (2 x 50 mL) .
  • the organic layers were combined and washed with brine (30 mL) , dried over anhydrous Na 2 SO 4 , concentrated under vacuum.
  • the resulting crude product was further purified by prep-HPLC with ACN/H 2 O (0.05%ammonium hydroxide) , Flow rate: 70 mL/min; Gradient: 35-55-55%B (2-19-25min) ; 212 nm; RT: 17.80-19.95 and 20.39-22.11.
  • Step 4 (4- ( (3- (7- ( (4-fluoro-1-methylpyrrolidin-3-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (13)
  • Step 1 tert-butyl 3-fluoro-3- ( (2-iodo-3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) carbamoyl) azetidine-1-carboxylate
  • Step 4 N- (2- (3- ( (4- (dimethylphosphoryl) -2-methoxyphenyl) amino) prop-1-yn-1-yl) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) -3-fluoro-1-methylazetidine-3-carboxamide (15)
  • thiophen-7-amine 0.530 g, 1.12 mmol
  • formaldehyde 0.228 g, 7.59 mmol
  • sodium cyanoboronhydride 0.283 g, 6.60 mmol
  • MeOH 5 mL
  • Step 4 (4- ( (3- (7- ( ( (4-fluoro-1-methylpiperidin-4-yl) methyl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (16)
  • Step 8 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (1, 1, 1-trifluoropropan-2-yl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (18) & (4- ( (3- (7- ( ( (3R, 4S) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (1, 1, 1-trifluoropropan-2-yl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (17)
  • the reaction mixture was stirred at 50 °C for 2 h. LCMS showed that the reaction was completed.
  • Step 1 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) propyl) amino) -3-methoxyphenyl) dimethylphosphine oxide (19)
  • Step 5 tert-butyl (S) -5- (dimethylphosphoryl) -2- (hydroxymethyl) indoline-1-carboxylate.
  • Step 7 tert-butyl (S) -5- (dimethylphosphoryl) -2-ethynylindoline-1-carboxylate.
  • Step 8 tert-butyl (S) -5- (dimethylphosphoryl) -2- ( (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) ethynyl) indoline-1-carboxylate
  • reaction was stirred under nitrogen atmosphere at RT for 3 h.
  • the reaction mixture was filtered through celite pad and celite pad was washed with ACN (3 x 10 mL) .
  • Step 9 (S) -2- ( (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) ethynyl) indolin-5-yl) dimethylphosphine oxide (21)
  • the mixture was concentrated to afford the crude product.
  • the crude product was purified by preparative HPLC (Mobile Phase A: water (0.05%ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 35-68-71%B (2-28-31min) ; 260 nm; 34.960-37.222) to provide the desired product.
  • Step 5 tert-butyl (R) -5- (dimethylphosphoryl) -2- (hydroxymethyl) indoline-1-carboxylate.
  • Step 7 tert-butyl (R) -5- (dimethylphosphoryl) -2-ethynylindoline-1-carboxylate.
  • Step 8 tert-butyl (R) -5- (dimethylphosphoryl) -2- ( (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) ethynyl) indoline-1-carboxylate
  • reaction was stirred under nitrogen atmosphere at RT for 3 h.
  • the reaction mixture was filtered through celite pad and the celite pad was washed with ACN (3 x 10 mL) .
  • Step 9 (R) -2- ( (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) ethynyl) indolin-5-yl) dimethylphosphine oxide (22)
  • the mixture was concentrated to afford the crude product.
  • the crude product was purified by preparative HPLC (Mobile Phase A: water (0.05%ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 35-68-71%B (2-28-31min) ; 260 nm; 34.960-37.222) to provide the desired product.
  • Step 4 (4-amino-3-methoxy-2- (methylthio) phenyl) dimethylphosphine oxide.
  • Step 5 (3-methoxy-2- (methylthio) -4- (prop-2-yn-1-ylamino) phenyl) dimethylphosphine oxide
  • Step 6 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxy-2- (methylthio) phenyl) dimethylphosphine oxide (23)
  • the reaction was stirred under nitrogen atmosphere at RT for 16 h.
  • the reaction mixture was filtered through celite pad and the celite pad was washed with ACN (3 x 20 mL) .
  • the filtrate was then concentrated under reduced pressure to afford the crude product.
  • the crude product was purified by preparative HPLC (Mobile Phase A: water (0.1%ammonium hydroxide) , Mobile Phase B: MeOH; Flow rate: 70 mL/min; Gradient: 35-70-95%B (2-30-60min) ; 254 nm; RT: 37.056-39.529) to provide the desired product.
  • Step 1 4- ( (3-methoxy-4-nitrophenyl) thio) tetrahydro-2H-pyran
  • Step 3 2, 2-trifluoro-N- ( (3-methoxy-4-nitrophenyl) (oxo) (tetrahydro-2H-pyran-4-yl) -l6-sulfaneylidene) acetamide
  • Step 5 2, 2-trifluoro-N- ( (3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) (oxo) (tetrahydro-2H-pyran-4-yl) -l6-sulfaneylidene) acetamide
  • reaction mixture was filtered through celite pad and celite pad was washed with ACN (3 x 20 mL) .
  • LCMS: m/z 405 [M+1] + .
  • Step 7 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (tetrahydro-2H-pyran-4-yl) -l6-sulfanone
  • the reaction was stirred under nitrogen atmosphere at RT for 16 h.
  • the reaction mixture was filtered through celite pad and the celite pad was washed with ACN (3 x 20 mL) .
  • the filtrate was then concentrated under reduced pressure to afford the crude product.
  • Step 8. (S) - (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (tetrahydro-2H-pyran-4-yl) -l6-sulfanone (24) and (R) - (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (tetrahydro-2H-pyran-4-yl) -l6-sulfanone (25)
  • Step 1 isopropyl (3-methoxy-4-nitrophenyl) sulfane
  • Step 3 2, 2-trifluoro-N- (isopropyl (3-methoxy-4-nitrophenyl) (oxo) -l6-sulfaneylidene) acetamide
  • Step 5 2, 2-trifluoro-N- (isopropyl (3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) (oxo) -l6-sulfaneylidene) acetamide
  • the reaction mixture was stirred under nitrogen at 50 °C for 16 h.
  • the reaction mixture was filtered through celite pad and the celite pad was washed with ACN (3 x 20 mL) .
  • LCMS: m/z 363 [M+1] + .
  • Step 7 (R) -imino (isopropyl) (3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) -l6-sulfanone and (S) -imino (isopropyl) (3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) -l6-sulfanone
  • Step 8 (S) - (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (isopropyl) -l6-sulfanone (27)
  • the reaction was stirred under nitrogen a tmosphere at RT for 16 h.
  • the crude product was purified by preparative HPLC (Mobile Phase A: water (0.05%ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 25-55-58%B (2-30-33min) ; 240 nm; 30.59-32.54) to provide the desired product.
  • Step 9 (R) - (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (isopropyl) -l6-sulfanone (26)
  • the reaction was stirred under nitrogen at mosphere at RT for 16 h.
  • the crude product was purified by preparative HPLC (Mobile Phase A: water (0.05%ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 70 mL/min; Gradient: 25-55-58%B (2-30-33min) ; 240 nm; 30.59-32.54) to provide the desired product.
  • Step 1 (3-methoxy-4- ( (3- (7- ( (1-methylpiperidin-3-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) phenyl) dimethylphosphine oxide.
  • Step 2 (R) - (3-methoxy-4- ( (3- (7- ( (1-methylpiperidin-3-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) phenyl) dimethylphosphine oxide (28) and (S) - (3-methoxy-4- ( (3- (7- ( (1-methylpiperidin-3-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) phenyl) dimethylphosphine oxide (29)
  • Step6 6- (dimethylphosphoryl) -3- (prop-2-yn-1-ylamino) picolinonitrile.
  • Step 1 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- ( (S) -2, 2, 2-trifluoro-1-hydroxyethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (31) , (4- ( (3- (7- ( ( (3R, 4S) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- ( (S) -2, 2, 2-trifluoro-1-hydroxyethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (32) , (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- ( (R)
  • the reaction was stirred at 60°C for 1 h under nitrogen.
  • the reaction was quenched with water (50 mL) , extracted with EA (2 x 50 mL) .
  • the organic layers were combined, washed with brine (2 x 100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the resulting crude product was further purified by pre-HPLC with MeOH/H 2 O (0.1%ammonium hydroxide) , Flow rate: 25 mL/min; Gradient: 50-85-100%B (2-30-60min); 270 nm; RT: 36.800-38.238/40.647-42.205) .
  • Step 1 (5- ( (3- (7- ( ( (3R, 4S) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -6-methoxypyridin-2-yl) dimethylphosphine oxide (37) .
  • the reaction was stirred at 60°C for 1 h under nitrogen.
  • the reaction was quenched with water (50 mL) , extracted with EA (2 x 50 mL) .
  • the organic layers were combined, washed with brine (2 x 100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the resulting crude product was further purified by pre-HPLC with ACN/H 2 O (0.05%ammonium hydroxide) , Flow rate: 70 mL/min; Gradient: 30-70-95%B (2-30-60 min) ; 265 nm; RT: 33.005-35.765) .
  • the reaction was quenched with saturated aqueous solution of NaHCO 3 (100 mL) , extracted with EA (3 x 100 mL) , The combined organic layers were washed with brine (500 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • Step3. (4- ( (3- (7- ( ( (3S, 4S) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (38) .
  • the reaction was stirred at 60 °C for 2 h under nitrogen.
  • the reaction was quenched with water (20 mL) , extracted with EA (30 mL) , The combined organic layers were washed with brine (30 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under vacuum.
  • the mixture was purified by preparative HPLC (Mobile Phase A: water (10 mmoL/L ammonium hydroxide) , Mobile Phase B: MeOH; Flow rate: 70 mL/min; Gradient: 50-90-100%B (2-30-40min) ; 270 nm; RT: 26.258-28.090 min) to provide the desired product.
  • Step 2 5- (dimethylphosphoryl) -2- (prop-2-yn-1-ylamino) benzonitrile.
  • Step 3 5- (dimethylphosphoryl) -N-hydroxy-2- (prop-2-yn-1-ylamino) benzimidamide.
  • Step 4 3- (5- (dimethylphosphoryl) -2- (prop-2-yn-1-ylamino) phenyl) -1, 2, 4-oxadiazol-5 (2H) -one.
  • Step 5 3- (5- (dimethylphosphoryl) -2- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) phenyl) -1, 2, 4-oxadiazol-5 (2H) -one (39) .
  • the reaction mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was completed.
  • the mixture was purified by prep-HPLC (Mobile Phase A: water (10 mmoL/L ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 35-69-69%B (2-30-60min) ; 266 nm; RT: 6.45 –7.91 min) .
  • Step 3 3-methoxy-4- (prop-2-yn-1-ylamino) benzonitrile.
  • Step 4 N-hydroxy-3-methoxy-4- (prop-2-yn-1-ylamino) benzimidamide.
  • Step 5 3- (3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) -1, 2, 4-oxadiazol-5 (2H) -one.
  • Step 3 (3-methoxy-2-methyl-4- (prop-2-yn-1-ylamino) phenyl) dimethylphosphine oxide.
  • Step 4 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxy-2-methylphenyl) dimethylphosphine oxide (41) .
  • Step 1 4-bromo-2-methoxy-3- (trifluoromethyl) aniline.
  • Step 2 (4-amino-3-methoxy-2- (trifluoromethyl) phenyl) dimethylphosphine oxide.
  • Step 3 (3-methoxy-4- (prop-2-yn-1-ylamino) -2- (trifluoromethyl) phenyl) dimethylphosphine oxide.
  • Step 4 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxy-2- (trifluoromethyl) phenyl) dimethylphosphine oxide (42) .
  • the reaction mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was completed.
  • the mixture was purified by prep-HPLC (Mobile Phase A: water (10 mmoL/L ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 25-75-75%B (2-30-60min) ; 266 nm; RT: 52.053 –53.667 min) .
  • Step 5 (4-amino-2-ethoxy-3-methoxyphenyl) dimethylphosphine oxide.
  • Step 6 (2-ethoxy-3-methoxy-4- (prop-2-yn-1-ylamino) phenyl) dimethylphosphine oxide.
  • Step 7 (2-ethoxy-4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) dimethylphosphine oxide (43) .
  • the reaction mixture was stirred at room temperature for 1 h. LCMS showed that the reaction was completed.
  • the mixture was purified by prep-HPLC (Mobile Phase A: water (10 mmoL/L ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 25-75-75%B (2-30-60min) ; 266 nm; RT: 52.053 –53.667 min) .
  • Step 2 imino (6-methoxy-5-nitropyridin-2-yl) (methyl) -l6-sulfanone.
  • Step 4.2 2, 2-trifluoro-N- ( (6-methoxy-5- (prop-2-yn-1-ylamino) pyridin-2-yl) (methyl) (oxo) -l6-sulfaneylidene) acetamide
  • Step 6 (5- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -6-methoxypyridin-2-yl) (imino) (methyl) -l6-sulfanone
  • Step 7 (S) - (5- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -6-methoxypyridin-2-yl) (imino) (methyl) -l6-sulfanone (45) and (R) - (5- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -6-methoxypyridin-2-yl) (imino) (methyl) -l6-sulfanone (44)
  • Step 1 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3- (methoxy-d3) phenyl) dimethylphosphine sulfide (47) .
  • LCMS showed that the reaction was completed.
  • the mixture was purified by prep-HPLC (Mobile Phase A: water (10 mmoL/L ammonium hydroxide) , Mobile Phase B: ACN; Flow rate: 40 mL/min; Gradient: 25-75-75%B (2-30-60min) ; 266 nm; RT: 52.053 –53.667 min) .
  • Step 1 N- (2-iodo-3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) quinuclidin-3-amine.
  • Step 2 (3-methoxy-4- ( (3- (7- (quinuclidin-3-ylamino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) phenyl) dimethylphosphine oxide.
  • N- (2-iodo-3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-7-yl) quinuclidin-3-amine (0.412 g, 0.88 mmol) , CuI (0.091 g, 0.51 mmol) , Pd (PPh 3 ) 2 Cl 2 (0.198 g, 0.272 mmol) , DIEA (0.318 g, 2.46 mmol) and DMF (5 mL) .
  • Step 3 (S) - (3-methoxy-4- ( (3- (7- (quinuclidin-3-ylamino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) phenyl) dimethylphosphine oxide (48) and (R) - (3-methoxy-4- ( (3- (7- (quinuclidin-3-ylamino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) phenyl) dimethylphosphine oxide (46)
  • Step 2 3- ( (3-methoxy-4-nitrophenyl) thio) oxetane.
  • Step 3 imino (3-methoxy-4-nitrophenyl) (oxetan-3-yl) -l6-sulfanone.
  • Step 4 tert-butyl ( (3-methoxy-4-nitrophenyl) (oxetan-3-yl) (oxo) -l6-sulfaneylidene) carbamate.
  • Step 7 tert-butyl ( (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (oxetan-3-yl) (oxo) -l6-sulfaneylidene) carbamate
  • Step 8 (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2 -yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (oxetan-3-yl) -l6-sulfanone
  • Step 9 (S) - (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (oxetan-3-yl) -l6-sulfanone (50) and (R) - (4- ( (3- (7-( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) (oxetan-3-yl) -l6-sulfanone (49)
  • Step 1 (difluoromethyl) (3-methoxy-4-nitrophenyl) sulfane.
  • Step 3 (4-amino-3-methoxyphenyl) (difluoromethyl) (imino) -l6-sulfanone.
  • Step 1 cyclopropyl (3-methoxy-4-nitrophenyl) sulfane.
  • Step 2 cyclopropyl (imino) (3-methoxy-4-nitrophenyl) -l6-sulfanone.
  • Step 3 N- (cyclopropyl (3-methoxy-4-nitrophenyl) (oxo) -l6-sulfaneylidene) -2, 2, 2-trifluoroacetamide.
  • Step 7 cyclopropyl (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) -l6-sulfanone
  • Step 8 (S) -cyclopropyl (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) -l6-sulfanone (54) and (R) -cyclopropyl (4- ( (3- (7- ( ( (3S, 4R) -3-fluoro-1-methylpiperidin-4-yl) amino) -3- (2, 2, 2-trifluoroethyl) benzo [b] thiophen-2-yl) prop-2-yn-1-yl) amino) -3-methoxyphenyl) (imino) -l6-sulfanone (53)

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) qui peuvent se lier à p53 mutant et restaurer la capacité du mutant de p53 à se lier à l'ADN et à activer des effecteurs en aval impliqués dans la suppression de tumeurs. L'invention concerne également des compositions pharmaceutiques comprenant les composés, des procédés de préparation des composés et des procédés d'utilisation des composés pour prévenir ou traiter une maladie ou un état associé à des mutants de p53.
PCT/CN2023/136981 2022-12-08 2023-12-07 Composés ciblant un mutant de p53 WO2024120471A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109069481A (zh) * 2016-02-19 2018-12-21 皮姆维制药公司 用于恢复突变p53功能的方法和化合物
WO2021262484A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Polythérapie pour le traitement du cancer
WO2021262483A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Méthodes et composés pour la restauration de la fonction du p53 mutant
WO2021262541A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Outil de diagnostic compagnon pour composés de réactivation de p53 mutantes
CN115003299A (zh) * 2019-09-23 2022-09-02 皮姆维制药公司 用于恢复突变体p53功能的方法和化合物
WO2023016434A1 (fr) * 2021-08-10 2023-02-16 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant un mutant de p53
CN115724784A (zh) * 2021-08-27 2023-03-03 杭州紫晶医药科技有限公司 作为p53调节剂和/或hdac抑制剂的化合物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109069481A (zh) * 2016-02-19 2018-12-21 皮姆维制药公司 用于恢复突变p53功能的方法和化合物
CN115003299A (zh) * 2019-09-23 2022-09-02 皮姆维制药公司 用于恢复突变体p53功能的方法和化合物
WO2021262484A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Polythérapie pour le traitement du cancer
WO2021262483A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Méthodes et composés pour la restauration de la fonction du p53 mutant
WO2021262541A1 (fr) * 2020-06-24 2021-12-30 Pmv Pharmaceuticals, Inc. Outil de diagnostic compagnon pour composés de réactivation de p53 mutantes
WO2023016434A1 (fr) * 2021-08-10 2023-02-16 Jacobio Pharmaceuticals Co., Ltd. Composés ciblant un mutant de p53
CN115724784A (zh) * 2021-08-27 2023-03-03 杭州紫晶医药科技有限公司 作为p53调节剂和/或hdac抑制剂的化合物

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