[go: up one dir, main page]

WO2025019585A1 - Inhibiteurs de kinases - Google Patents

Inhibiteurs de kinases Download PDF

Info

Publication number
WO2025019585A1
WO2025019585A1 PCT/US2024/038376 US2024038376W WO2025019585A1 WO 2025019585 A1 WO2025019585 A1 WO 2025019585A1 US 2024038376 W US2024038376 W US 2024038376W WO 2025019585 A1 WO2025019585 A1 WO 2025019585A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
heterocycloalkyl
cycloalkyl
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/038376
Other languages
English (en)
Inventor
Barry R. O'keefe
Lin Du
Brice A.P. WILSON
Ping Zhang
Dongdong Wang
Juliana A. MARTINEZ FIESCO
Ning Li
William J. Moore
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
US Department of Health and Human Services
Original Assignee
US Department of Health and Human Services
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by US Department of Health and Human Services filed Critical US Department of Health and Human Services
Publication of WO2025019585A1 publication Critical patent/WO2025019585A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • kinases that are associated with cell functions such as cell signaling, metabolism, and division. Some kinases have been found to be more active in certain types of cancers. Blocking the kinases associated with cancer growth may provide therapeutic advantages to those suffering from cancer. Given that cancer is currently a major health concern and that there is a lack of effective treatments against all cancers, there is an urgent need to identify new kinase inhibitors to treat cancers. There is also an urgent need to identify kinase inhibitors associated with non-cancer pathologies (e.g., infections) in order to treat conditions and disorders associated with non-cancer pathologies.
  • non-cancer pathologies e.g., infections
  • NCI National Cancer Institute
  • NPNPD NCI Program for Natural Product Discovery
  • a class of active compounds identified were isolated from the marine organism Aplidium sp. These compounds, named Aplithianines A & B, were shown to potently inhibit both (1) oncogenic gene fusion DNAJB1-PRKACA (PKADJ) and (2) wild type protein kinase A (PKA) at nanomolar concentrations.
  • PKADJ oncogenic gene fusion DNAJB1-PRKACA
  • PKA wild type protein kinase A
  • Aplithianine A was shown to potently and selectively inhibit a broad range of kinases, not just PKADJ or PKA, broadening its potential utility. Further kinetic analysis showed that Aplithianine A was a competitive inhibitor of kinases, competing with ATP for binding to PKA. Additional structural studies showed that aplithianine A bound to the catalytic pocket in PKADJ where ATP normally binds, further proving the competitive mechanism of inhibition and providing structural insights for further synthetic modification of this compound class.
  • the aplithianine structural class is a group of potent kinase inhibitors with broad potential applicability to numerous kinases of importance, e.g., for cancer chemotherapy.
  • gene fusions a genetic lesion ligating two normally non-adjacent portions of the genome next to one another
  • Approximately 20% of all solid malignancies have at least one identifiable gene fusion.
  • imatmib The experience with the BCR-ABL1 kinase inhibitor imatmib (Savage, et al.. Ai Engl. J. Med..
  • FL-HCC fibrolamellar hepatocellular carcinoma
  • DNAJ fusion complexes may present novel small molecule binding sites which can be exploited for the treatment of FL-HCC (Tomasmi, et al., Scientific Reports, 8: 720 (2016); Cheung, et al., PEAS USA, 112: 1374-7S? (2015); and Averill, et al., J. Cell Biochem., 120: 13783-91 (2019)).
  • FL-HCC Tomasmi, et al., Scientific Reports, 8: 720 (2018); Cheung, et al., PEAS USA, 112: 1374-7S? (2015); and Averill, et al., J. Cell Biochem., 120: 13783-91 (2019)).
  • the invention provides compounds of formula (I): wherein X’, X 2 , X 3 , xzzzzr, R ! , and A are defined herein, or a pharmaceutically acceptable salt thereof.
  • the invention provides compounds of formula (II):
  • the invention also provides pharmaceutical compositions comprising compounds of formula (I) or formula (11).
  • the invention further provides methods of inhibiting kinase activity in a subject, methods of suppressing the immune system in a subject, methods of preventing organ rejection in a subject, methods of treating cancer in a subject, methods of treating diabetic neuropathic pain in a subject, methods of treating malaria in a subject, and/or methods of treating an infection associated with a protozoa in a subject comprising administering to the subject compounds or pharmaceutical compositions of aspects of the present invention.
  • FIG. 1 is a graph showing the normalized % JPKAca Activity curve for compound Compound GS.
  • FIG. 2 is a graph showing the normalized % JPKAca Activity curve for compound Compound JV.
  • FIG. 3 is a graph showing the normalized % JPKAca Activity curve for compound Compound JN.
  • FIG. 4 is a graph showing the normalized % JPKAca Activity curve for compound Compound JB.
  • FIG. 5 is a graph showing the normalized % JPKAca Activity curve for compound Compound IX.
  • FIG.6 is a graph showing the normalized % JPKAc ⁇ Activity curve for compound Compound IW.
  • FIG.7 is a graph showing the normalized % JPKAc ⁇ Activity curve for compound Compound GX.
  • FIG.8 is a graph showing the IC 50 value reproducibility across three separate trial runs for select compounds of Example 12.
  • FIG.9 shows the NCI-60 human tumor cell line screen results for Compound BO.
  • FIG.10 shows the NCI-60 human tumor cell line screen results for Compound BJ.
  • X 1 and X 2 are each independently CH, CR 4 , or N;
  • R 1 is H or –NR 2 R 3 ;
  • R 2 is H or C 1 -C 3 alkyl;
  • R 3 is an aryl;
  • R 4 is C 1 -C 3 alkyl;
  • A is –NR5((CHR7)mR6);
  • R 5 , R 6 , and R 7 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)- NH 2 , C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycl
  • the compound of formula (I) is of formula (Ia): O S A or a pharmaceutically accepta .
  • the compound of formula (I) is of formula (Ib): O A or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is of formula (Ic): O S A or a pharmaceutically accepta .
  • the compound of formula (I) is of formula (Id): O A or a pharmaceutically acceptable salt thereof.
  • the compound of formula (I) is of formula (Ie): O S A or a pharmaceutically accepta .
  • the compound of formula (I) is of formula (In): O A or a pharmaceutically acceptable salt thereof.
  • A is a nitrogen bound C 3 -C 8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from each of which is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C1- C 6 alkoxy, -C(O)OH, -C(O)O-(C 1 -C 6 alkyl), -C(O)-(C 1 -C 6 alkyl), -(C 1 -C 3 alkyl)-C(O)OH,
  • A is a nitrogen bound C3-C8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 - C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C 1 -C 6 alkyl)-NH 2 , halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl
  • A comprises a nitrogen bound C3-C8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, trifluoromethyl, C1-C6 alkoxy, arylated C1-C6 alkoxy, trifluoromethylated C 1 -C 6 alkoxy, -C(O)OH, -C(O)O-(C 1 -C 6 alkyl), -C(O)-(C 1 -C 6 alkyl), - (C1-C3 alkyl)-C(O)OH, -(C1-C3 alkyl)-C(O)O-(C1-C6 alkyl), -(C1-C
  • A comprises a C 3 -C 8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C2-C6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 cycloalkyl)-OH, -(C 1 -C 6 alkyl)- COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C1-C6 alkylamino, di-C1-C6 alkyl- amino; –NH-aryl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocycloalkyl, fuse
  • A comprises at least one nitrogen atom (e.g., at least two nitrogen atoms or at least three nitrogen atoms). In certain embodiments, A contains exactly 1 nitrogen atom. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises at least two nitrogen atoms. In certain embodiments, A contains exactly 2 nitrogen atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A comprises at least 3 (e.g., 3-10, 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms.
  • A comprises at least five (e.g., 5-10, 6-10, 7-10, 5-12, 6-12, or 7- 12) carbon atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), A contains only carbon, nitrogen, oxygen, and hydrogen atoms.
  • A contains only carbon, nitrogen, sulfur, and hydrogen atoms.
  • A fulfills the following requirements: (i) A comprises a C 3 -C 8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents, (ii) A comprises at least two nitrogen atoms, (iii) A comprises at least five (e.g., 5-10, 6-10, 7-10, 5-12, 6-12, or 7-12) carbon atoms, and (iv) A contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom.
  • any of the aspects described herein of the compound a of formula (I) is a single bond. diments (i.e., any of the aspects described herein) of the compound a of formula (I), is a double bond. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), m is 0. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), R 1 is H. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), R 7 is H.
  • m is 1 and R 7 is H.
  • X 1 and X 2 are not both N.
  • X 1 and X 2 are each independently CH or CR 4 .
  • X 1 and X 2 are each independently CH.
  • the compound of formula (I) is of formula (If): O NH 2 S R 8 , wherein X 1 and X 2 are each independently CH, CR 4 , or N; R 1 is H or –NR 2 R 3 ; R 2 is H or C1-C3 alkyl; R 3 is an aryl; R 4 is C1-C3 alkyl; R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -(C 1 -C 6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino; –
  • the compound of formula (I) is of formula (Ig): O S NH 2 , wherein X 1 and X 2 are each independently CH, CR 4 , or N; R 1 is H or –NR 2 R 3 ; R 2 is H or C1-C3 alkyl; R 3 is an aryl; R 4 is C1-C3 alkyl; R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -(C 1 -C 6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino; – NH
  • the compound of formula (I) is of formula (Ih): O S H R 8 , wherein X 1 and X 2 are each independently CH, CR 4 , or N; R 1 is H or –NR 2 R 3 ; R 2 is H or C1-C3 alkyl; R 3 is an aryl; R 4 is C1-C3 alkyl; R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -(C 1 -C 6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino; – NH
  • the compound of formula (I) is of formula (Ij): O R 8 , wherein X 1 and X 2 are each independently CH, CR 4 , or N; R 1 is H or –NR 2 R 3 ; R 2 is H or C1-C3 alkyl; R 3 is an aryl; R 4 is C1-C3 alkyl; R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -(C 1 -C 6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino; –NH-aryl
  • R8 is hydrogen.
  • the compound of formula (I) is of formula (Ik): R 8 O H 2 , wherein X 1 and X 2 are each independently CH, CR 4 , or N; R 1 is H or –NR 2 R 3 ; R 2 is H or C 1 -C 3 alkyl; R 3 is an aryl; R 4 is C 1 -C 3 alkyl; R8 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino
  • X 1 and X 2 are each independently CH, CR 4 , or N;
  • R 1 is H or –NR 2 R 3 ;
  • R 2 is H or C1-C3 alkyl;
  • R 3 is an aryl;
  • R 4 is C1-C3 alkyl;
  • R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, -(C 1 -C 6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino; –NH-aryl, C 1 -C 6 haloalkyl, C 3 -
  • the compound of formula (I) is not one or more of the following compounds:
  • the compound of formula (II) is of formula (IIa): S E R1 or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is of formula (IIb): S E R1 or a pharmaceutically acceptab
  • the compound of formula (II) is of formula (IIc): S E R1 or a pharmaceutically acceptable salt thereof.
  • the compound of formula (II) is of formula (IId): S E R1 or a pharmaceutically acceptab
  • the compound of formula (II) is of formula (IIe): S E R1 or a pharmaceutically acceptabl
  • the compound of formula (II) is of formula (IIf):
  • E is selected from: H N N N HN O S HN NH O S NH NH N N , , O , each of which is optionally substituted with one or more substituents selected from C1-C6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, trifluoromethyl, C 1 -C 6 alkoxy, arylated C 1 -C 6 alkoxy, trifluoromethylated C1-C6 alkoxy, -C(O)OH, -C(O)O-(C1-C6 alkyl), -C(O)-(C1-C6 alkyl), - (C 1 -C 3 alkyl)-C(O)OH, -(C 1 -C 3 alkyl)-C(O)O-(C 1 -C
  • E is selected from: H N N N HN O S HN NH O S NH NH N , , each of which is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)- OH, -(C 1 -C 6 alkyl)-COOH, -(C 1 -C 6 alkyl)-NH 2 , halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 hetero
  • E comprises at least one nitrogen atom (e.g., at least two nitrogen atoms or at least three nitrogen atoms). In certain embodiments, E contains exactly 1 nitrogen atom. In other embodiments, E contains exactly 2 nitrogen atoms. In some embodiments, E contains exactly 3 nitrogen atoms. In some embodiments (i.e., any of the aspects described herein) of the compound of formula (I), E comprises at least 3 (e.g., 3-10, 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms.
  • E comprises at least 4 (e.g., 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6- 12, or 7-12) carbon atoms.
  • E contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom.
  • E contains only carbon, nitrogen, oxygen, and hydrogen atoms.
  • E contains only carbon, nitrogen, sulfur, and hydrogen atoms.
  • E fulfills the following requirements: (i) E comprises at least one nitrogen atom (e.g., at least two nitrogen atoms), and (ii) E comprises at least 3 (e.g., 3-10, 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms.
  • E fulfills the following requirements: (i) E comprises at least one nitrogen atom (e.g., at least two nitrogen atoms), (ii) E comprises at least 4 (e.g., 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms, and (iii) E contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom.
  • E comprises at least one nitrogen atom (e.g., at least two nitrogen atoms)
  • E comprises at least 4 (e.g., 4-10, 5-10, 6-10, 7-10, 4-12, 5-12, 6-12, or 7-12) carbon atoms
  • E contains only carbon, nitrogen, and hydrogen atoms, e.g., does not contain an oxygen atom.
  • the compound a of formula (II) is a single bond.
  • any of the aspects described herein of the compound a of formula (II) is a double bond.
  • R 1 is H.
  • X 1 and X 2 are not both N.
  • X 1 and X 2 are each independently CH or CR 4 .
  • X 1 and X 2 are each independently CH.
  • the compound of formula (II) is:
  • the compound of formula (II) is not one or more of the following compounds: H 3 C Br H 3 C N H 3 C N O N N S N N S , or Any of the compounds of formula (I) and formula (II) can exist as any suitable stereoisomer thereof.
  • the invention provides enantiomers and diastereomers of any of the compounds disclosed herein.
  • any of the compounds of formula (I) and formula (II) can exist as a racemic mixture and/or a mixture of diastereomers.
  • alkyl implies a straight-chain or branched alkyl substituent containing from, for example, from about 1 to about 6 carbon atoms, e.g., from about 1 to about 4 carbon atoms.
  • alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert- butyl, n-pentyl, isopentyl, n-hexyl, and the like.
  • alkyl occurs as part of a group, such as, e.g., in C 3 -C 6 cycloalkylalkyl, hydroxyalkyl, haloalkyl (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, alkylamino, dialkylamino, alkylaminoalkyl, dialkylaminoalkyl, arylcarbonylalkyl (-(alkyl)C(O)aryl), arylalkyl, etc.
  • the alkyl can be substituted or unsubstituted, as described herein.
  • alkyl is an alkylene chain (e.g., -(CH 2 ) n -)
  • the alkyl group can be substituted or unsubstituted.
  • alkenyl means a linear alkenyl substituent containing from, for example, about 2 to about 6 carbon atoms (branched alkenyls are about 3 to about 6 carbon atoms), e.g., from about 3 to about 5 carbon atoms (branched alkenyls are about 3 to about 6 carbon atoms).
  • the alkenyl group is a C 2 -C 4 alkenyl.
  • alkenyl group examples include ethenyl, allyl, 2-propenyl, 1-butenyl, 2-butenyl, 1- pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, and the like.
  • the alkenyl can be substituted or unsubstituted, as described herein.
  • cycloalkyl as used herein, means a cyclic alkyl moiety containing from, for example, 3 to 6 carbon atoms or from 5 to 6 carbon atoms.
  • the cycloalkyl can be substituted or unsubstituted, as described herein.
  • the cycloalkyl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e, sharing two atoms and a bond with a neighboring substituent.
  • aryl refers to a mono, bi, or tricyclic carbocyclic ring system having one, two, or three aromatic rings, for example, phenyl, naphthyl, anthracenyl, or biphenyl.
  • aryl refers to an unsubstituted or substituted aromatic carbocyclic moiety, as commonly understood in the art, and includes monocyclic and polycyclic aromatics such as, for example, phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl, and the like.
  • the aryl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e,. sharing two atoms and a bond with a neighboring substituent.
  • a neighboring substituent e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl
  • heteroaryl refers to aromatic 5 or 6 membered monocyclic groups, 9 or 10 membered bicyclic groups, and 11 to 14 membered tricyclic groups which have at least one heteroatom (O, S, or N) in at least one of the rings.
  • Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms and/or from one to four nitrogen atoms provided that the total number of heteroatoms in each ring is four or less and each ring has at least one carbon atom.
  • the fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
  • the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may optionally be quaternized.
  • Heteroaryl groups which are bicyclic or tricyclic must include at least one fully aromatic ring but the other fused ring or rings may be aromatic or non-aromatic.
  • the heteroaryl group may be attached at any available nitrogen or carbon atom of any ring.
  • Illustrative examples of heteroaryl groups are pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl, imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxazolyl, and oxadiazolyl.
  • the heteroaryl can be substituted or unsubstituted, as described herein.
  • heteroaryl may also be fused to a neighboring substituent (e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl), i.e,. sharing two atoms and a bond with a neighboring substituent.
  • a neighboring substituent e.g., a cycloalkyl, a heterocycloalkyl, an aryl, or a heteroaryl
  • heterocycloalkyl means a stable, saturated, or partially unsaturated monocyclic, bicyclic, and spiro ring system containing 3 to 7 ring members of carbon atoms and other atoms selected from nitrogen, sulfur, and/or oxygen.
  • a heterocycloalkyl is a 5, 6, or 7- membered monocyclic ring and contains one, two, or three heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the heterocycloalkyl may be attached to the parent structure through a carbon atom or through any heteroatom of the heterocycloalkyl that results in a stable structure.
  • heterocycloalkyl rings examples include isoxazolyl, thiazolinyl, imidazolidinyl, piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl.
  • the heterocycloalkyl can be substituted or unsubstituted, as described herein.
  • the term “C8-C10 bicycloalkyl” refers to an aryl group fused to a cycloalkyl group, as described herein.
  • C4-C10 biheterocycloalkyl refers to an aryl group fused to a heterocycloalkyl group, a heteroaryl group fused to a heterocycloalkyl group, or a heteroaryl group fused to a cycloalkyl group, as described herein.
  • fused means that the indicated ring system shares a bond with the ring system to which it is attached.
  • the term “spiro” means that the indicated ring system shares an atom with the ring system to which it is attached.
  • the term “hydroxy” refers to the group –OH.
  • the term “cyano” refers to the group –CN, whereas the term “thiocyano” refers to -SCN.
  • alkoxy and cycloalkyloxy embrace linear or branched alkyl and cycloalkyl groups, respectively, that are attached to a divalent oxygen.
  • the alkyl and cycloalkyl groups are the same as described herein.
  • halo refers to a halogen selected from fluorine, chlorine, bromine, and iodine.
  • carboxylato refers to the group -C(O)OH.
  • the term “amino” refers to the group –NH2.
  • alkylamino refers to —NHR
  • dialkylamino refers to –NRR’.
  • R and R' are the same or different and each is a substituted or unsubstituted alkyl group, as described herein.
  • the term “amido” refers to the group -C(O)NRR’, which R and R’ are the same or different and each is hydrogen or a substituted or unsubstituted alkyl group, as described herein.
  • phosphonato refers to the group -P(O)(OR) 2 , which R is hydrogen or a substituted or unsubstituted alkyl group, as described herein.
  • amino acid refers to any amino acid selected from alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine.
  • the amino acid when used as a substituent, is alanine or glycine. In certain embodiments, when used as a substituent, the amino acid is nitrogen bound.
  • amino acid methyl ester refers to any amino acid described herein that has been converted to the methyl ester.
  • any substituent that is not hydrogen e.g., C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, or heterocycloalkylalkyl
  • the substituted moiety typically comprises at least one substituent (e.g., 1, 2, 3, 4, 5, 6, etc.) in any suitable position (e.g., 1-, 2-, 3-, 4-, 5-, or 6-position, etc.).
  • substituent e.g., 1, 2, 3, 4, 5, 6, etc.
  • any suitable position e.g., 1-, 2-, 3-, 4-, 5-, or 6-position, etc.
  • an aryl group is substituted with a substituent, e.g., halo, amino, alkyl, OH, alkoxy, and others
  • the aromatic ring hydrogen is replaced with the substituent and this can take place in any of the available hydrogens, e.g., 2, 3, 4, 5, and/or 6-position wherein the 1-position is the point of attachment of the aryl group in the compound of the present invention.
  • Suitable substituents include, e.g., halo, alkyl, alkenyl, hydroxy, nitro, cyano, amino, alkylamino, alkoxy, aryloxy, aralkoxy, carboxyl, carboxyalkyl, carboxyalkyloxy, amido, alkylamido, haloalkylamido, aryl, heteroaryl, heterocycloalkyl, cycloalkyl, fused aryl, fused heteroaryl, fused heterocycloalkyl, and fused cycloalkyl, each of which is described herein.
  • the substituent is at least one alkyl, halo, and/or haloalkyl (e.g., 1 or 2).
  • a range of the number of atoms in a structure is indicated (e.g., a C1-12, C1-8, C1-6, C1-4, etc.), it is specifically contemplated that any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • a range of 1- 8 carbon atoms e.g., C 1 -C 8
  • 1-6 carbon atoms e.g., C 1 -C 6
  • 1-4 carbon atoms e.g., C 1 -C 4
  • 1-3 carbon atoms e.g., C1-C3
  • 2-8 carbon atoms e.g., C2-C8
  • any chemical group e.g., alkyl, cycloalkyl, etc.
  • any sub-range thereof e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms
  • salts or “pharmaceutically acceptable salt” is intended to include nontoxic salts synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • an inorganic acid e.g., hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid
  • an organic acid e.g., oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic acid, methylsulfonic acid, or benzylsulfonic acid
  • an inorganic base e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or ammonium hydroxide
  • an organic base e.g., methylamine, diethylamine, triethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, guanidine, choline, or cinchonine
  • an amino acid e.g., lysine, arginine, or alanine
  • nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical.
  • Lists of suitable salts are found in Remington’s Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p.1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977).
  • they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt.
  • the salt is a trifluoroacetate salt.
  • the pharmaceutical compositions contain a pharmaceutically acceptable carrier.
  • the pharmaceutical composition of the present invention can comprise a compound of formula (I) and/or a compound of formula (II), or a pharmaceutically acceptable salt thereof.
  • the compound has a purity of at least about 85% (e.g., at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9%).
  • the pharmaceutical composition can comprise a compound of the present invention (e.g., a compound of formula (I) and/or a compound of formula (II)) in combination with one or more other pharmaceutically active agents or drugs, such as a chemotherapeutic agent, e.g., a topoisomerase I inhibitor, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituximab, vinblastine, vincristine, etc.
  • a chemotherapeutic agent e.g., a topoisomerase I inhibitor, asparaginase, busulfan, carboplatin, cisplatin, daunorubicin, doxorubicin, fluorouracil, gemcitabine, hydroxyurea, methotrexate, paclitaxel, rituxim
  • the carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the active compound(s), and by the route of administration.
  • the pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, and diluents, are well-known to those skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active agent(s) and one which has no detrimental side effects or toxicity under the conditions of use. [0108]
  • the choice of carrier will be determined in part by the particular compounds, as well as by the particular method used to administer the compounds.
  • suitable formulations of the pharmaceutical composition of the invention can be administered in any suitable manner (e.g., orally, intravenously, intramuscularly, intrathecally, subcutaneously, sublingually, buccally, rectally, vaginally, by ocular route, by otic route, nasally, by inhalation, by nebulization, topically, systemically, transdermally, or a combination thereof).
  • the pharmaceutical composition of the invention is administered orally.
  • the following formulations for administration are exemplary and are in no way limiting.
  • Formulations suitable for administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compounds can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol or hexadecyl alcohol, a glycol, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol, ketals such as 2,2-dimethyl-1,3-dioxolane- 4-methanol, ethers, poly(ethyleneglycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.
  • Oils which can be used in formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl- ⁇ -aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • cationic detergents such as,
  • the formulations will typically contain from about 0.5% to about 25% by weight of the compounds in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17.
  • HLB hydrophile-lipophile balance
  • the quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight.
  • Suitable surfactants include polyethylene glycol sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • the formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the requirements for effective pharmaceutical carriers for compositions are well-known to those of ordinary skill in the art (see, e.g., Lloyd et al. (eds.), Remington: The Science and Practice of Pharmacy, 22nd Ed., Pharmaceutical Press (2012)).
  • the compounds of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • the amount or dose of the compounds administered should be sufficient to effect a desired response, e.g., a therapeutic or prophylactic response, in the mammal over a reasonable time frame.
  • the dose of the compounds should be sufficient to inhibit growth of a target cell or treat or prevent cancer in a period of from about 2 hours or longer, e.g., 12 to 24 or more hours, from the time of administration. In certain aspects, the time period could be even longer.
  • the dose will be determined by the efficacy of the particular compounds and the condition of the mammal (e.g., human), as well as the body weight of the mammal (e.g., human) to be treated.
  • An administered dose may be determined in vitro (e.g., cell cultures) or in vivo (e.g., animal studies). For example, an administered dose may be determined by determining the IC 50 (the dose that achieves a half-maximal inhibition of symptoms), LD50 (the dose lethal to 50% of the population), the ED 50 (the dose therapeutically effective in 50% of the population), and the therapeutic index in cell culture and/or animal studies.
  • the therapeutic index is the ratio of LD 50 to ED 50 (i.e., LD 50 /ED 50 ).
  • the dose of the compounds also will be determined by the existence, nature, and extent of any adverse side effects that might accompany the administration of a particular compound. Typically, the attending physician will decide the dosage of the compounds with which to treat each individual patient, taking into consideration a variety of factors, such as age, body weight, general health, diet, sex, compounds to be administered, route of administration, and the severity of the condition being treated.
  • the dose of the compounds can be about 0.001 to about 1000 mg/kg body weight of the subject being treated/day, from about 0.01 to about 10 mg/kg body weight/day, about 0.01 mg to about 1 mg/kg body weight/day, from about 1 to about to about 1000 mg/kg body weight/day, from about 5 to about 500 mg/kg body weight/day, from about 10 to about 250 mg/kg body weight/day, about 25 to about 150 mg/kg body weight/day, or about 10 mg/kg body weight/day.
  • the concentration of the compounds in the pharmaceutical composition is at least 0.05 mg/ml (e.g., at least about 0.1 mg/ml, at least about 0.2 mg/ml, at least about 0.5 mg/ml, or at least about 1 mg/ml). This concentration is greater than the naturally occurring concentration of the compounds in their natural environment (e.g., in a sea sponge).
  • Methods of Use [0119] In an aspect, the invention provides methods of inhibiting kinase activity in a subject, the method comprising administering to the subject a compound or pharmaceutical composition of the invention.
  • the kinase is a PKA, a PKG, a PKC, a STK, a CLK, a DYRK, or LATS.
  • the kinase is PKA, PKA/DNAJ, cAMP-PKA, PKG1a, PKG1b, PKG2, PfPKG, PKC- ⁇ , PKC-nu, PKC-d, PKC-eta, PKC-g, STK39, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, LATS1, or LATS2.
  • the kinase is PKA, PKA/DNAJ, PKG1a, PKG1b, PKG2, PKC- ⁇ , PKC-nu, PKC-d, PKC-eta, PKC-g, STK39, CLK1, CLK2, CLK3, CLK4, DYRK1A, DYRK1B, DYRK2, DYRK3, DYRK4, LATS1, or LATS2.
  • the kinase is PKA, PKA/DNAJ, or cAMP-PKA.
  • the kinase is protein kinase A (PKA).
  • PKA is inhibited resulting in therapeutic benefits to the subject.
  • PKA is inhibited resulting in treatment of a cancer.
  • PKA is inhibited resulting in treatment of liver cancer, for example, hepatocellular carcinoma (HCC) and fibrolamellar hepatocellular carcinoma.
  • HCC hepatocellular carcinoma
  • fibrolamellar hepatocellular carcinoma fibrolamellar hepatocellular carcinoma.
  • PKA is inhibited resulting in treatment of diabetic neuropathic pain (Ma, et al., Neuroscience Letters, 750: 135763 (2021)).
  • the kinase is PKA/DNAJ.
  • PKA/DNAJ is inhibited resulting in therapeutic benefits to the subject.
  • PKA/DNAJ is inhibited resulting in treatment of a cancer.
  • PKA/DNAJ is inhibited resulting in treatment of liver cancer, for example, hepatocellular carcinoma (HCC) and fibrolamellar hepatocellular carcinoma.
  • PKA/DNAJ is inhibited resulting in treatment of diabetic neuropathic pain.
  • the kinase is cyclic adenosine monophosphate- protein kinase A (cAMP-PKA).
  • cAMP-PKA is inhibited resulting in therapeutic benefits to the subject.
  • cAMP-PKA is inhibited resulting in treatment of a cancer.
  • cAMP-PKA is inhibited resulting in treatment of liver cancer, for example, hepatocellular carcinoma (HCC) and fibrolamellar hepatocellular carcinoma.
  • cAMP-PKA is inhibited resulting in treatment of diabetic neuropathic pain.
  • the kinase inhibited by compounds of aspects of the invention is a protein kinase G (PKG).
  • PKG protein kinase G
  • a PKG is inhibited resulting in therapeutic benefits to the subject.
  • a PKG is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer (Wu, et al., Molecular Medicine Reports, 14: 1849-1856 (2016); Islam, et al., Carcinogenesis, 43(6): 584–593 (2022)).
  • a PKG is inhibited resulting in treatment and/or prevention of an infection, for example, a parasite infection, for example, malaria (i.e., infection caused by a Plasmodium) (Eck, et al., ChemBioChem, 23(7): 1-8 (2022)).
  • the kinase is PKG1a, PKG1b, PKG2, or PfPKG.
  • the kinase is PKG1a.
  • PKG1a is inhibited resulting in therapeutic benefits to the subject.
  • PKG1a is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer.
  • PKG1a is inhibited resulting in treatment and/or prevention of an infection, for example, malaria.
  • the kinase is PKG1b. In an aspect, PKG1b is inhibited resulting in therapeutic benefits to the subject.
  • PKG1b is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, PKG1b is inhibited resulting in treatment and/or prevention of an infection, for example, malaria.
  • the kinase is PKG2. In an aspect, PKG2 is inhibited resulting in therapeutic benefits to the subject. In an aspect, PKG2 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, PKG2 is inhibited resulting in treatment and/or prevention of an infection, for example, malaria.
  • the kinase is PfPKG.
  • the kinase is a protein kinase C (PKC).
  • PKC protein kinase C
  • a PKC is inhibited resulting in therapeutic benefits to the subject.
  • a PKC is inhibited resulting in treatment of a cancer.
  • the kinase is PKC- ⁇ , PKC-nu, PKC-d, PKC-eta, or PKC-g.
  • the kinase is PKC- ⁇ . In an aspect of the invention, the kinase is PKC-nu. In an aspect of the invention, the kinase is PKC-d. In an aspect of the invention, the kinase is PKC-eta. In an aspect of the invention, the kinase is PKC-g. [0135] In some aspects of the invention, the kinase is a serine/threonine kinase (STK). In an aspect, a STK is inhibited resulting in therapeutic benefits to the subject. In an aspect, a STK is inhibited resulting in treatment of a cancer, for example, breast cancer.
  • STK serine/threonine kinase
  • the kinase is STK39.
  • STK39 is inhibited resulting in therapeutic benefits to the subject.
  • STK39 is inhibited resulting in treatment of a cancer, for example, breast cancer.
  • the kinase inhibited by compounds of aspects of the invention is a dual-specificity tyrosine-regulated kinase (DYRK).
  • DYRK dual-specificity tyrosine-regulated kinase
  • a DYRK is inhibited resulting in therapeutic benefits to the subject.
  • a DYRK is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer (Boni, et al., Cancers, 12: 1-26 (2020); Henderson, et al., J. Med. Chem., 64: 11709 ⁇ 11728 (2021)).
  • a DYRK is inhibited resulting in treatment and/or prevention of an infection, for example, an infection caused by a protozoa (Loa ⁇ c, et al., Mar. Drugs, 15(316): 1-15 (2017)) or parasite (e.g., Trypanosoma brucei; Cayla, et al., eLife, 1-34 (2020)).
  • the kinase is DYRK1A, DYRK1B, DYRK2, DYRK3, or DYRK4. [0139] In some aspects of the invention, the kinase is DYRK1A. In an aspect, DYRK1A is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK1A is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK1A is inhibited resulting in treatment and/or prevention of an infection, for example, an infection caused by a protozoa or parasite.
  • the kinase is DYRK1B. In an aspect, DYRK1B is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK1B is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK1B is inhibited resulting in treatment and/or prevention of an infection, for example, an infection caused by a protozoa or parasite. [0141] In some aspects of the invention, the kinase is DYRK2. In an aspect, DYRK2 is inhibited resulting in therapeutic benefits to the subject.
  • DYRK2 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer. In an aspect, DYRK2 is inhibited resulting in treatment and/or prevention of an infection, for example, an infection caused by a protozoa or parasite.
  • the kinase is DYRK3. In an aspect, DYRK3 is inhibited resulting in therapeutic benefits to the subject. In an aspect, DYRK3 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer.
  • DYRK3 is inhibited resulting in treatment and/or prevention of an infection, for example, an infection caused by a protozoa or parasite.
  • the kinase is DYRK4.
  • DYRK4 is inhibited resulting in therapeutic benefits to the subject.
  • DYRK4 is inhibited resulting in treatment of a cancer, for example, gastric cancer or colon cancer.
  • DYRK4 is inhibited resulting in treatment and/or prevention of an infection, for example, an infection caused by a protozoa or parasite.
  • the kinase inhibited by compounds of aspects of the invention is a Cdc2-like kinase (CLK).
  • CLK Cdc2-like kinase
  • a CLK is inhibited resulting in therapeutic benefits to the subject.
  • a CLK is inhibited resulting in treatment of cancer.
  • a CLK is inhibited resulting in treatment of gastric cancer (Tam, et al., Cancer Letters, 473: 186–197 (2020)), pancreatic cancer (Chen, et al., J. Hematol.
  • a CLK is inhibited resulting in treatment or prevention of memory impairments and neurotoxicityinduced by oligomeric A ⁇ 25–35 peptide administration
  • a CLK is inhibited resulting in treatment or prevention of arthritis, e.g., osteoarthritis (e.g., knee osteoarthritis) (Sun, et al., J. Med. Chem., 67: 6, 4603–4623 (2024)).
  • a CLK is inhibited resulting in treatment or prevention of arthritis, e.g., osteoarthritis (e.g., knee osteoarthritis).
  • the compounds of aspects of the invention modulate RNA splicing.
  • a CLK is inhibited resulting in therapeutic mRNA splicing modulation.
  • the kinase is CLK1, CLK2, CLK3, or CLK4.
  • CLK1 is inhibited resulting in therapeutic benefits to the subject.
  • CLK1 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK1 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric A ⁇ 25–35 peptide administration.
  • CLK2 is inhibited resulting in therapeutic benefits to the subject. In an aspect, CLK2 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK2 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric A ⁇ 25–35 peptide administration.
  • CLK3 is inhibited resulting in therapeutic benefits to the subject.
  • CLK3 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK3 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric A ⁇ 25–35 peptide administration. [0150] In some aspects of the invention, CLK4 is inhibited resulting in therapeutic benefits to the subject. In an aspect, CLK4 is inhibited resulting in treatment of a cancer, for example, gastric cancer. In an aspect, CLK4 is inhibited resulting in prevention of memory impairments and neurotoxicity induced by oligomeric A ⁇ 25–35 peptide administration.
  • the kinase inhibited by compounds of aspects of the invention is a LATS (Large Tumor Suppressor Kinase).
  • a LATS is inhibited resulting in therapeutic benefits to the subject.
  • a LATS is inhibited resulting in treatment of a cancer.
  • the kinase inhibited by compounds of aspects of the invention is LATS1 (Large Tumor Suppressor Kinase 1).
  • LATS1 is inhibited resulting in therapeutic benefits to the subject.
  • a LATS1 is inhibited resulting in treatment of a cancer.
  • the kinase inhibited by compounds of aspects of the invention is LATS2 (Large Tumor Suppressor Kinase 2).
  • LATS2 is inhibited resulting in therapeutic benefits to the subject.
  • a LATS2 is inhibited resulting in treatment of a cancer.
  • the invention provides methods of suppressing the immune system in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods preventing organ rejection in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating diabetic neuropathic pain in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating malaria in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating an infection associated with a protozoa in a subject, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating a neurodegenerative disease, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating Down syndrome, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating Alzheimer's disease, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating cardiac disease, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating heart failure, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating Cushing’s syndrome, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating McCune-Albright Syndrome, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • the invention provides methods of treating Carney complex, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, or pharmaceutical composition of an aspect of the invention.
  • An aspect of the invention provides compounds and pharmaceutically compositions for use in treating or preventing cancer.
  • the compounds inhibit kinases.
  • the methods of an aspect of the invention can provide any amount of any level of treatment or prevention of cancer in a mammal.
  • the treatment or prevention provided by the method of an aspect of the invention can include treatment or prevention of one or more conditions or symptoms of the disease, e.g., cancer, being treated or prevented.
  • the cancer can be any cancer, including any of adrenal gland cancer, sarcomas (e.g., synovial sarcoma, osteogenic sarcoma, leiomyosarcoma uteri, angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, and teratoma), lymphomas (e.g., small lymphocytic lymphoma, Hodgkin lymphoma, and non-Hodgkin lymphoma), hepatocellular carcinoma, glioma, head cancers (e.g., squamous cell carcinoma), neck cancers (e.g., squamous cell carcinoma), acute lympho
  • sarcomas e.g., synovial sarcoma, osteogenic sarcoma, leiomyosarcoma uteri, angio
  • the cancer is hepatocellular carcinoma.
  • the cancer is fibrolamellar carcinoma (FLC).
  • the cancer is fibrolamellar hepatocellular carcinoma (FL-HCC).
  • the cancer is liver cancer.
  • the cancer is breast cancer (e.g., triple negative breast cancer).
  • the cancer is gastric cancer.
  • the cancer is colon cancer.
  • the cancer is prostate canceer.
  • the cancer in pancreatic cancer.
  • the cancer is a glioma.
  • the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof can be co-administered with an anti-cancer agent (e.g., a chemotherapeutic agent) and/or radiation therapy.
  • an anti-cancer agent e.g., a chemotherapeutic agent
  • the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof are administered in an amount that is effective to sensitize the cancer cells to one or more therapeutic regimens (e.g., chemotherapy or radiation therapy).
  • therapeutic regimens e.g., chemotherapy or radiation therapy.
  • co-administered” or “co-administration” refer to simultaneous or sequential administration.
  • the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof can be administered before, concurrently with, or after administration of another anti-cancer agent (e.g., a chemotherapeutic agent).
  • One or more than one, e.g., two, three, or more anti-cancer agents can be administered.
  • the present invention is directed a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a combination of the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof, and at least one anti- cancer agent (e.g., chemotherapeutic agent).
  • anti-cancer agents include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mitomycin C, plicamycin, dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine, and
  • the anti- cancer agent is cisplatin, cytarabine, methotrexate, doxorubicin, or a combination thereof.
  • the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof can be attached to targeting molecules.
  • targeting molecules include antibodies (for ADCs) and small molecules that target other regions of kinases to afford more selectivity (i.e., a second molecule that binds the DNAJ domain of the PKADJ fusion protein).
  • the compounds of aspects of the invention, or pharmaceutically acceptable salts thereof can be attached to an E3 ligase binding molecule to make a proteolysis-targeting chimeras (PROTAC).
  • PROTAC proteolysis-targeting chimeras
  • the subject is a mammal.
  • mammal refers to any mammal, including, but not limited to, mammals of the order Rodentia, including mice and hamsters, mammals of the order Logomorpha, including rabbits, mammals from the order Carnivora, including Felines (cats) and Canines (dogs), mammals from the order Artiodactyla, including Bovines (cows) and Swines (pigs), mammals from the order Perssodactyla, including Equines (horses), mammals of the order Primates, Ceboids, or Simoids (monkeys), and mammals of the order Anthropoids (humans and apes).
  • An especially preferred mammal is the human.
  • X 1 and X 2 are each independently CH, CR 4 , or N;
  • R 1 is H or –NR 2 R 3 ;
  • R 2 is H or C1-C3 alkyl;
  • R 3 is an aryl;
  • R 4 is C1-C3 alkyl;
  • A is –NR 5 R 6 ;
  • R5 and R6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, -(C 1 -C 6 alkyl)-OH, -(C 1 -C 6 cycloalkyl)-OH, -(C 1 -C 6 alkyl)-COOH, -(C 1 -C 6 alkyl)- NH2, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, aryl,
  • A comprises a C 3 -C 8 heterocycloalkyl or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, - (C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C1-C6 alkyl)-NH2, halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkyl-amino; –NH-aryl, C 1 -C 6 haloalkyl, C
  • X 1 and X 2 are each independently CH, CR 4 , or N;
  • R 3 is an aryl;
  • R 4 is C 1 -C 3 alkyl;
  • E is a carbon bound C3-C8 heterocycloalkyl, aryl, or heteroaryl group, each of which is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)-OH, -(C1-C6 alkyl)-COOH, -(C 1 -C 6 alkyl)-NH 2 , halo, nitro, hydroxy, amino, C 1 -C 6 alkyl)-NH 2 , halo, nitro,
  • E is selected from: , each of which is optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C1-C6 alkyl)-OH, -(C1-C6 cycloalkyl)- OH, -(C 1 -C 6 alkyl)-COOH, -(C 1 -C 6 alkyl)-NH 2 , halo, nitro, hydroxy, amino, C 1 -C 6 alkylamino, di-C1-C6 alkyl-amino; –NH-aryl, C1-C6 haloalkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, fused C 3 -C 8 cycloalkyl, fused C 3 -C 8 heteroalkyl, fused C 3 -C 8 heteroalkyl,
  • [0202] (29) A method of preventing organ rejection in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.
  • [0203] (30) A method of treating cancer in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.
  • [0204] (31) The method of aspect 30, wherein the cancer is fibrolamellar carcinoma (FLC).
  • FLC fibrolamellar carcinoma
  • FL-HCC fibrolamellar hepatocellular carcinoma
  • [0206] (33) The method of aspect 30, wherein the cancer is gastric cancer, colon cancer, pancreatic cancer, prostate cancer, breast cancer, lung cancer, or gliomas.
  • [0207] (34) A method of modulating mRNA splicing in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.
  • [0208] (35) A method of treating diabetic neuropathic pain in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject.
  • [0209] (36) A method of treating malaria in a subject, the method comprising administering to the subject a compound of any one of aspects 1-20 or the pharmaceutical composition of aspect 21 to the subject. [0210] (37) A method of treating an infection associated with a protozoa in a subject, the method comprising administering to the subject a compound of any one of aspects 1-21 or the pharmaceutical composition of aspect 20 to the subject. [0211] (38) The method of any one of aspects 22-37, wherein the subject is human. EXAMPLES [0212] All solvents were of LC-MS grade or better.
  • NMR data were obtained on a Bruker Avance III NMR spectrometer equipped with a 3 mm cryogenic probe (600 MHz for 1 H, 150 MHz for 13 C).
  • Specimens of the tunicate Aplidium sp. were collected from a reef in South Africa in September 2000, and kept frozen until extraction. The collection was carried out by the Coral Reef Research Foundation under contract with the Natural Products Branch, U.S. National Cancer Institute. A voucher specimen (voucher ID # 0CDN7423) was deposited at the Smithsonian Institution, Washington, D.C.
  • the catalyst XPhos-PdG3 (0.05 mmol) was added under argon, and the resulting reaction mixture was irradiated by microwave at 120 °C for 1 h. The reaction progress was monitored by UPLC- MS until complete consumption of starting material was observed. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude compound was purified by a mass directed auto purification system using reverse phase chromatography to afford the desired target.
  • Condition-B To a stirred solution of bromo derivative (1 mmol) in 1,4-dioxane (30 vol.) and water (10 vol.) was added boronic acid or boronate ester (1.2 mmol) and Na 2 CO 3 (3 mmol) and the resulting reaction mixture was purged with argon for 5 min. The catalyst XPhos-PdG3 (0.05 mmol) was added under argon, and the resulting reaction mixture was stirred at 100 °C for 18 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was cooled to room temperature and concentrated under reduced pressure.
  • Condition-B To a stirred solution of acid derivative (1 mmol) in methylene chloride (50 vol.), was added triethylamine (3 mmol) and the requisite amine (1.2 mmol). The resulting reaction mixture was stirred for 5 min. N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide hydrochloride (1.5 mmol) and 1-hydroxybenzotriazole hydrate (1.5 mmol) was added under argon, and the resulting reaction mixture was stirred at room temperature for 16 h.
  • Condition-E To a stirred solution of a Boc protected derivative (1 mmol) in 1,4- dioxane (5 vol.) was added 4 M hydrochloric acid in 1,4-dioxane (2 vol.) at 0 °C and the resulting reaction mixture was warmed to room temperature and stirred for 2 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was lyophilized from a solution of acetonitrile and water to afford the desired target.
  • Condition-F To a stirred solution of a Boc protected derivative (1 mmol) in trifluoroethanol (5 vol.) was added trimethylsilyl chloride (1 vol.) at 0 °C and the resulting reaction mixture was stirred at room temperature for 2 h. The reaction progress was monitored by UPLC-MS until complete consumption of starting material was observed. The reaction mixture was concentrated under reduced pressure. The crude compound was lyophilized from a solution of acetonitrile and water to afford the desired target.
  • 6-(1H-Indazol-6-yl)-4-(9H-purin-6-y H-1,4-thiazine was prepared using a Suzuki reaction with the appropriate boronicacid by following condition-A. Off-white solid. Yield: 9%.
  • EXAMPLE 2 This example provides an exemplary synthesis for Compounds V-AO, DP-DS, DU, DZ, YA, YB, YD-YF, YJ-YO, and YR-YU. [0268] Starting materials Bromo-SEM-Scaffold and Bromo-Scaffold-B were prepared using the synthetic protocol set forth in Scheme 3.
  • the resulting reaction mixture was warmed to room temperature and stirred for 2 h.
  • the reaction mixture was concentrated under reduced pressure.
  • the crude intermediate was dissolved in methanol and added ammonia solution (35% in water) at below 10 °C (while adding ammonia solution solid formation was observed) and stirring was continued at room temperature for 18 h.
  • the reaction progress was monitored by TLC until complete consumption of starting material was observed.
  • the resulting solution was stirred at room temperature for 3 h.
  • the reaction progress was monitored by thin layer chromatography and UPLC-MS.
  • the reaction mixture was concentrated under reduced pressure.
  • the obtained residue was dissolved in methanol (2.00 mL), and then ammonium hydroxide solution (2.00 mL) was added to the reaction mixture.
  • the reaction mixture was concentrated under reduced pressure to obtain the crude which was dissolved in methanol (0.20 mL).
  • Aqueous ammonium hydroxide solution (0.20 mL) was added at 0 oC.
  • the resulting solution was stirred at room temperature for 16 h.
  • the reaction mixture was concentrated under reduced pressure.
  • the crude compound was purified by using prep-HPLC purification to afford 5-(4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2-(pyridin-3-yl)oxazole (4.00 mg, 13%, IN-RVN-F-17) as a yellow solid.
  • the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS.
  • the reaction mixture was diluted with water (10.0 mL) and extracted with dichloromethane (10.0 mL). The organic extracts were washed with water (10.0 mL) and brine (10.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get tert-butyl 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- pyrazol-1-yl)acetyl)piperazine-1-carboxylate (75.0 mg, crude) as a light brown solid.
  • the resulting reaction mixture was stirred at room temperature for 16 h.
  • the reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (2 ⁇ 50.0 mL).
  • the combined extracts were washed with water (20.0 mL), brine solution (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude compound was purified by flash chromatography with silica gel, eluting with 4% to 6% methanol in dichloromethane.
  • the reaction mixture was concentrated under reduced pressure to obtain the crude which was dissolved in methanol (0.20 mL). Aqueous ammonium hydroxide solution (0.20 mL) was added at 0 oC. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The crude compound was purified by using prep-HPLC purification to afford 5-(4- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)-2-(pyridin-3-yl)oxazole (4.0 mg, 12) as a yellow solid.
  • the resulting reaction mixture was stirred at room temperature for 16 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (2 ⁇ 50.0 mL).
  • the resulting reaction mixture was stirred at room temperature for 3 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS.
  • the reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (2 ⁇ 50.0 mL). The combined organic extracts were washed with water (50.0 mL), brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get 2-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) ethyl methane sulfonate (0.55 g, crude) as an off-white solid.
  • the reaction mixture was diluted with water (30.0 mL) and extracted with dichloromethane (2 ⁇ 30.0 mL). The combined organic extracts were washed with water (30.0 mL), brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to get N-methyl-2-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl) ethan-1-amine (0.10 g, crude) as a viscous material. The crude product was used for the next step without further purification.
  • the resulting reaction mixture was warmed to room temperature and stirred for 2 h.
  • the reaction mixture was concentrated under reduced pressure.
  • the obtained intermediate was dissolved in methanol (30.00 mL), added ammonia solution (50.0 mL, 35% in water) at below 10 °C (while adding ammonia solution solid formation was observed) and stirring was continued further at room temperature for 18 h.
  • the reaction progress monitored by TLC until complete consumption of starting material was observed.
  • tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (2) To a stirred solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (10.0 g, 49.7 mmol) in dichloromethane (100 mL) was added triethylamine (13.85 mL, 99.36 mmol) and methane sulfonyl chloride (4.61 mL, 59.6 mmol) at 0 °C. The reaction was stirred at room temperature for 2 h, and then the progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was diluted with dichloromethane (100 mL), washed with water (2 ⁇ 50 mL) and brine solution (2 ⁇ 50 mL), dried over from sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material.
  • the crude material was purified by flash chromatography using silica gel, and eluting with 9% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford tert-butyl 4- ((methylsulfonyl)oxy)piperidine-1-carboxylate (12.5 g, 90%) as an off-white solid.
  • the reaction mixture was poured into ice-cold water (40.0 mL) and extracted with methyl tert-butyl ether (2 ⁇ 60.0 mL). The combined organic extracts were washed with ice cold water (60.0 mL), brine (60.0 mL), dried over from sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography, eluting with 11% ethyl acetate in hexanes.
  • the progress of the reaction was monitored by thin layer chromatography and UPLC-MS.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride solution (30.0 mL) and extracted ethyl acetate (2 ⁇ 60.0 mL).
  • the combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude material was purified by flash silica gel column chromatography, eluting with 11% ethyl acetate in hexanes.
  • the reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was diluted with dichloromethane (100 mL), washed with water (2 ⁇ 50 mL), brine solution (2 ⁇ 50 mL), dried over from sodium sulfate, filtered and concentrated under reduced pressure to obtain crude material.
  • the crude material was purified by flash chromatography using silica gel, eluting with 6% ethyl acetate in hexanes. The pure fractions were concentrated under reduced pressure to afford tert-butyl 3- ((methylsulfonyl)oxy)piperidine-1-carboxylate (6.70 g, 97%) as an off-white solid.
  • the reaction mixture was cooled to room temperature poured into ice-cold water (60.0 mL). This mixture was extracted with methyl tert-butyl ether (2 ⁇ 60.0 mL). The combined organic extracts were washed with ice cold water (100.0 mL), brine (100.0 mL), dried over from sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash silica gel column chromatography, eluting with 8% ethyl acetate in hexanes.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride solution (30.0 mL) and extracted with ethyl acetate (2 ⁇ 30.0 mL). The combined organic extracts were washed with brine (30.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude material was purified by flash silica gel column chromatography, eluting with 9% ethyl acetate in hexanes. The pure fractions were collected and concentrated under reduced pressure to afford tert-butyl 3-(4- bromo-2H-1,2,3-triazol-2-yl)piperidine-1-carboxylate (0.88 g, 66) as pale yellow solid.
  • EXAMPLE 5 This example provides an exemplary synthesis for Compounds BJ-BW, DM, and YV.
  • Acid Scaffold-A was synthesized from the commercially available H-1 and H-2. In particular, H-1 was reacted with H-2 in presence of Xantphos Pd G3 and Cs 2 CO 3 to afford H-3, which was reacted with KOH to afford Acid Scaffold-A, as set forth in Scheme 24.
  • Acid Scaffold-B was synthesized from the commercially available H-1 and H-4.
  • H-1 was reacted with H-4 in presence of Xantphos Pd G3 and Cs 2 CO 3 to afford H-5 which was reacted with KOH to afford Acid Scaffold-B, as set forth in Scheme 25.
  • Bromo Scaffold-A was synthesized from Acid Scaffold-A, as set forth in Scheme 26.
  • Scheme 26 Preparation of Bromo Scaffold-A of Example 5
  • Bromo Scaffold-B was synthesized from Acid Scaffold-B, as set forth in Scheme 27.
  • Scheme 27 Preparation of Bromo Scaffold-B of Example 5 [0413] Preparation of py , py n-4-yl)-3,4-dihydro-2H-1,4- thiazine (Bromo scaffold-B): A reaction vial containing a DMF (6 mL) solution of Acid scaffold-B (1 equiv., 30 mg)) was filled with N 2 and cooled down in an ice bath.
  • EXAMPLE 6 This example provides an exemplary synthesis for Compounds BX-DL. Compounds BX-DL are synthesized using the methods described in Examples 1-5.
  • EXAMPLE 7 [0432] This example provides an exemplary synthesis for Compounds EA-EJ. [0433] Synthesis of Thiazine Amide Products. Each of the following compounds was synthesized by the general procedure for Amide Coupling set forth in Scheme 29. Scheme 29: General Procedure for Amide Coupling of Example 7 diamines (1.5 equiv.) was added HATU (1.5 equiv.), DIPEA (10 equiv.), and DMF. The reaction mixture was then stirred vigorously at room temperature overnight before it was dried down under vacuum.
  • EXAMPLE 8 This example provides an exemplary synthesis for Compounds EK-GO, OT-OY, QJ-QL, and QN.
  • Starting material Acid Scaffold-A was prepared using the synthetic protocol set forth in Scheme 30.
  • Scheme 30 Preparation of 4-(9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid (Acid Scaffold-A) of Example 8 Potassium carbonate (40.20 g, 291.2 mmol) was added to a stirred solution of 6-chloro-9H- purine (15.0 g, 97.1 mmol) in anhydrous dimethylformamide (400 mL) at room temperature.
  • the reaction mixture was cooled to below 10 °C and 2-(trimethylsilyl)ethoxymethyl chloride (26.20 mL, 145.6 mmol) was added dropwise over a period of 15 min.
  • the reaction mixture was warmed to room temperature and stirring was continued for 24 h.
  • the progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was poured into ice-cold water (1.50 L) and extracted with ethyl acetate (3 ⁇ 150 mL). The combined organic layers were washed with a brine solution (3 ⁇ 50 mL), dried over sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to obtain the crude material as a pale-yellow solid.
  • the material was purified by flash chromatography by using silica gel (230-400 mesh). The desired product was eluted with 20-25% ethyl acetate/hexanes. The pure fractions were collected and concentrated under reduced pressure to afford 6-chloro-9- ((2-(trimethylsilyl)ethoxy)methyl)-9H-purine (14.70 g, 53%) as colourless oil which solidified upon standing overnight.
  • the reaction mixture was stirred at 120 °C for 3 h. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS.
  • the reaction mixture was cooled to room temperature and diluted with cold water (1.0 L). The solid that formed was collected by filtration and washed with excess cold water (500 mL). The solids were dried under vacuum to afford ethyl 4-(9-((2-(trimethylsilyl)ethoxy)methyl)-9H-purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6- carboxylate [13.48 g (crude)] as an off-white solid.
  • Rel-N-((1S,3S)-3-hydroxy-2,3-dihydro-1H-inden-1-yl)-4-(9H- purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide (Compound FU): Rel-N-((1S,3S)-3-hydroxy-2,3-dihy -(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide was prepared with the appropriate benzoyl protected amine by using condition-C (43.0 mg; 25%). The benzoyl derivative was deprotected using condition- G. Off white solid.
  • Rel-N-((1R,3S)-3-hydroxy-2,3-dihydro-1H-inden-1-yl)-4-(9H- purin-6-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxamide (Compound FW): Rel-N-((1R,3S)-3-hydroxy-2,3-dihy -(9H-purin-6-yl)-3,4-dihydro-2H- 1,4-thiazine-6-carboxamide was prepared with the appropriate benzoyl protected amine by using condition-C (36.0 mg; 20%). The benzoyl derivative was deprotected using condition- G. Off white solid.
  • EXAMPLE 9 This example provides an exemplary synthesis for Compounds GP-IU, OZ-PB, PE, PF, PH, PJ, PK, QM, QO-QR, RR-RT, RV, RW, RZ, SA, SC, SK, SM-SO, TA, TD-TF, TL, TM, TO-TR, TV, TY, UQ-UW, VF-VL, VN, VO, VS-WP.
  • Starting material Acid Scaffold-B was prepared using the synthetic protocol set forth in Scheme 32.
  • the reaction mixture was stirred at room temperature for 30 min, the progress of the reaction was monitored by TLC.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride solution (100 mL) and diluted with ice-water (100 mL).
  • the resulted solution was extracted with methyl tert-butyl ether (2 ⁇ 100 mL).
  • the combined organic layers were washed with brine solution (3 ⁇ 50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure.
  • the obtained crude material was purified by flash chromatography by using silica gel (230- 400 mesh).
  • the resulting reaction mixture was stirred at 95 °C for 4 h, progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was concentrated under reduced pressure to obtain crude material which was diluted with water (300 mL) acidified with 10% aqueous citric acid solution (pH ⁇ 4).
  • the obtained solid material was filtered and solid cake was washed with excess cold water and dried to afford 4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazine-6-carboxylic acid [7.50 g, (crude)] as an off- white solid.
  • Acid Scaffold-B was transformed into Compounds GP-IU, OZ-PB, PE, PF, PH, PJ, PK, QM, QQ, QR, RR-RT, RV, RW, RZ, SA, SC, SK, SM-SO, TA, TD-TF, TL, TM, TO-TR, TV, TY, UQ-UW, VF-VL, VN, VO, VS, VU, VW, VY, and WH using the general synthetic protocol for amide targets set forth in Scheme 33.
  • the resulting reaction mixture was heated to 80 °C and stirred for 4 h. The reaction progress was monitored by thin layer chromatography. The reaction mixture was concentrated under reduced pressure to obtain the crude material which was diluted with water (20.0 mL) and neutralized with 10% aqueous citric acid solution. The resulting solution was extracted with ethyl acetate (2 ⁇ 100 mL).
  • tert-butyl (R)-piperidin-3-ylcarbamate (0.91 g, 4.6 mmol) was added to the reaction mixture at room temperature. The resulting mixture was stirred at the same temperature for 24 h. The reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (2 ⁇ 20.0 mL). The combined organic extracts were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using 100-200 silica gel and eluting with 50% ethyl acetate in hexanes.
  • the reaction mixture was stirred at room temperature for 4 h.
  • the reaction mixture was concentrated under reduced pressure to give a crude residue which was dissolved in methanol (20.0 mL) and 25% aqueous ammonia (5.0 mL) was added at 0 °C.
  • the observed precipitate was stirred at room temperature for 16 h.
  • the reaction mixture was cooled to 0 °C and the solid collected by filtration. The solid cake was washed with cold methanol (5.0 mL).
  • reaction mixture was stirred at room temperature for 16 h, and then sodium cyanoborohydride (0.40 g, 6.40 mmol) was added to the reaction mixture at 0 °C.
  • the resulting solution was stirred at room temperature for 3 h.
  • the reaction progress was monitored by thin layer chromatography.
  • the reaction mixture was concentrated under reduced pressure to obtain the crude material which was diluted with ice water (50.0 mL) and extracted with dichloromethane (2 ⁇ 100 mL).
  • tert-butyl (R)-(1- methylpiperidin-4-yl)(piperidin-3-yl)carbamate (226 mg, 0.76 mmol) was added to the reaction mixture. The resulting mixture was stirred at the same temperature for 16 h. The reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (2 ⁇ 20 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash chromatography using 100-200 silica gel and eluting with 5% methanol in dichloromethane.
  • reaction mixture was stirred at room temperature for 2 h. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B:10 mm ammonium bicarbonate in water).
  • the resulting reaction mixture was stirred at room temperature for 4 h. The reaction progress was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure to obtain the crude mixture which was diluted with water (20.0 mL), neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate (2 ⁇ 50.0 mL). The combined organic extracts were washed with water (50.0 mL), brine solution (50.0 mL), dried over sodium sulfate and concentrated under reduced pressure to give crude which was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile.
  • tert-butyl (2R,4R)-2-(aminomethyl)-4- hydroxypyrrolidine-1-carboxylate (0.82 g, 3.8 mmol) was added. The mixture was stirred at the same temperature for 16 h. The reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (2 ⁇ 20 mL). The combined organic extracts were washed brine (20.0 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified by flash chromatography using 100-200 silica gel and eluting with 80% ethyl acetate in hexanes.
  • the reaction mixture was stirred at room temperature for 4 h.
  • the reaction mixture was concentrated under reduced pressure to give crude which was dissolved in methanol (2.0 mL) and added 25% aqueous ammonia (0.50 mL) at 0 °C.
  • the obtained precipitate was stirred at room temperature for 16 h.
  • the reaction was concentrated under reduced pressure.
  • the crude material was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B:10 mm ammonium bicarbonate in water).
  • the reaction mixture was stirred at room temperature for 16 h.
  • the reaction mixture was diluted with water (50.0 mL) and extracted with dichloromethane (2 ⁇ 50 mL). The combined organic extracts were washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography using silica gel and eluting with 60% ethyl acetate in hexanes.
  • the progress of the reaction was monitored by thin layer chromatography and UPLC-MS.
  • the reaction mixture was cooled to 0 °C, quenched with saturated ammonium chloride solution (50.0 mL) and extracted with ethyl acetate (2 ⁇ 40.0 mL). The combined organic extracts were washed with brine (40.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography using silica gel and eluting with 40% ethyl acetate in hexanes.
  • reaction mixture was stirred at the same temperature for 60 min. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by preparative HPLC (Column: Gemini NX- C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B: 0.05% FA in water).
  • the reaction mixture was stirred for 16 h.
  • the reaction mixture was diluted with water (20.0 mL) and extracted with dichloromethane (2 ⁇ 20.0 mL).
  • the combined organic extracts were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography using silica gel and eluting with 30% ethyl acetate in hexanes.
  • the progress of the reaction was monitored by thin layer chromatography and UPLC-MS.
  • the reaction mixture was cooled to 0 °C and quenched with saturated ammonium chloride solution (50.0 mL) and then extracted with ethyl acetate (2 ⁇ 50.0 mL). The combined organic extracts were washed with brine (50.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure.
  • the crude material was purified by flash chromatography using silica gel and eluting with 30% ethyl acetate in hexanes.
  • the reaction mixture was concentrated under reduced pressure and the crude residue was diluted with water (10.0 mL) and extracted with 10% methanol: dichloromethane (2 ⁇ 20.0 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure.
  • the crude material was purified by flash chromatography using silica gel and eluting with 7-8% methanol in dichloromethane. The pure fractions were combined and concentrated under reduced pressure to afford tert-butyl (2R,4R)-2-(amino(phenyl)methyl)-4- methoxypyrrolidine-1-carboxylate (60.0 mg, 20%) as an off-white solid.
  • reaction mixture was stirred at the same temperature for 60 min. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B: 0.05% FA in water).
  • reaction mixture was stirred at the same temperature for 60 min. The progress of the reaction was monitored by thin layer chromatography and UPLC- MS. The reaction mixture was concentrated under reduced pressure. The crude material was triturated with 10% tert-butyl methyl ether in acetonitrile to afford (4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-3,4-dihydro-2H-1,4-thiazin-6-yl)((3R,4S)-3-amino-4- (hydroxymethyl)piperidin-1-yl)methanone hydrochloride (45.2 g, 88%) as an off-white solid.
  • reaction mixture was stirred at the same temperature for 60 min. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B:10 mm Ammonium bicarbonate in water).
  • the reaction mixture was warmed to room temperature and stirred for 16 h.
  • the reaction mixture was concentrated under reduced pressure to give the crude mixture which was diluted with water (10.0 mL), cooled to 0 °C and acidified up to pH ⁇ 5 with 10% aqueous citric acid solution.
  • the resulted solution was extracted with ethyl acetate (2 ⁇ 20.0 mL).
  • reaction mixture was stirred at the same temperature for 60 min. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure, and the crude material was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B:10 mm Ammonium bicarbonate in water).
  • the reaction mixture was warmed to room temperature and stirred for 16 h.
  • the reaction mixture was diluted with water (20.0 mL) and extracted with methyl tert-butyl ether (2 ⁇ 20.0 mL).
  • the combined organic extracts were washed with brine (20.0 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give the 1-(tert-butyl) 4-ethyl (3R,4R)-3- ((((9H-fluoren-9-yl)methoxy)carbonyl)amino)piperidine-1,4-dicarboxylate (1.40 g) as an off- white solid.
  • the crude product was directly used for the next step without further purification.
  • the reaction mixture was warmed to room temperature and stirred for 16 h.
  • the reaction mixture was concentrated under reduced pressure to give the crude mixture which was diluted with water (10.0 mL), cooled to 0 °C and acidified up to pH ⁇ 5 with 10% aqueous citric acid solution.
  • the resulted solution was extracted with ethyl acetate (2 ⁇ 20.0 mL).
  • the combined organic extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure.
  • the crude material was purified by preparative HPLC (Column: Gemini NX-C18 10 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile.
  • Mobile Phase B 10 mm Ammonium bicarbonate in water.
  • reaction mixture was warmed to room temperature and stirred for 30 minutes, and then the reaction mixture was heated to 70 °C and stirred for 2 h. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure to obtain the crude product which was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B:10 mm Ammonium bicarbonate in water).
  • reaction mixture was warmed to room temperature and stirred for 30 minutes, and then the reaction was heated to 70 °C and stirred for 2 h. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was quenched with saturated ammonium chloride solution (10.0 mL) and extracted with ethyl acetate (2 ⁇ 20.0 mL).
  • reaction mixture was warmed to room temperature and stirred for 30 minutes, and then the reaction mixture was heated to 70 °C and stirred for 2 h. The progress of the reaction was monitored by thin layer chromatography and UPLC-MS. The reaction mixture was concentrated under reduced pressure to obtain the crude material which was purified by preparative HPLC (Column: Gemini NX-C1810 mm 150 ⁇ 30 mm, 10mm. Mobile Phase A: acetonitrile. Mobile Phase B:10 mm Ammonium bicarbonate in water).
  • reaction mixture was stirred at room temperature for 6 h, progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was poured into an ice cold saturated aqueous ammonium chloride solution (100 mL) and the product was extracted with methyl tert-butyl ether (2 ⁇ 100 mL). The combined organic layers were washed with cold brine solution (3 ⁇ 50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the obtained crude material was purified by flash chromatography by using silica gel (230-400 mesh). The desired product was eluted with 20- 25% ethyl acetate in hexanes.
  • reaction mixture was stirred at 120 °C for 4 h, progress of the reaction was monitored by thin layer chromatography.
  • the reaction mixture was cooled to room temperature, diluted with cold water (400 mL) and extracted with methyl tert-butyl ether (3 ⁇ 150 mL). The combined organic layers were washed with cold brine solution (3 ⁇ 100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to get the crude material which was purified by flash chromatography by using silica gel (230-400 mesh). The desired product was eluted with 20-25% ethyl acetate in hexanes.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une classe d'inhibiteurs de kinases de formule (I) ou de formule (II). L'invention concerne également des compositions pharmaceutiques associées et des procédés d'utilisation des inhibiteurs de kinases.
PCT/US2024/038376 2023-07-17 2024-07-17 Inhibiteurs de kinases Pending WO2025019585A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363527274P 2023-07-17 2023-07-17
US63/527,274 2023-07-17

Publications (1)

Publication Number Publication Date
WO2025019585A1 true WO2025019585A1 (fr) 2025-01-23

Family

ID=92583082

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/038376 Pending WO2025019585A1 (fr) 2023-07-17 2024-07-17 Inhibiteurs de kinases

Country Status (1)

Country Link
WO (1) WO2025019585A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001973A1 (fr) * 2012-06-29 2014-01-03 Pfizer Inc. Nouvelles 7h-pyrrolo[2,3-d]pyrimidines substituées par un groupe amino en position 4, utilisées comme inhibiteurs de lrrk2
WO2024020333A2 (fr) * 2022-07-17 2024-01-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de kinases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014001973A1 (fr) * 2012-06-29 2014-01-03 Pfizer Inc. Nouvelles 7h-pyrrolo[2,3-d]pyrimidines substituées par un groupe amino en position 4, utilisées comme inhibiteurs de lrrk2
WO2024020333A2 (fr) * 2022-07-17 2024-01-25 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs de kinases

Similar Documents

Publication Publication Date Title
US11702418B2 (en) SOS1 inhibitors
CN112166110B (zh) Shp2磷酸酶抑制剂及其使用方法
EP2892899B1 (fr) Inhibiteurs de jak3 de type imidazopyridazine et leur utilisation pour le traitement de maladies inflammatoires et auto-immunes
ES2808987T3 (es) Lactamas fusionadas con arilo y heteroarilo
AU2016240033B2 (en) 1-cyano-pyrrolidine compounds as USP30 inhibitors
AU2011253057B2 (en) Nitrogen heterocyclic compounds useful as PDE10 inhibitors
TWI457339B (zh) 稠合雜芳香環吡咯啶酮
KR101862493B1 (ko) Fgfr4 억제제로서의 고리-융합된 비시클릭 피리딜 유도체
AU2017289315B2 (en) Heteroaromatic derivatives as NIK inhibitors
KR101659193B1 (ko) Btk 활성의 억제제로서의 헤테로아릴 피리돈 및 아자-피리돈 화합물
WO2022015375A1 (fr) Inhibiteurs de kras g12d
AU2017288755B2 (en) Novel compound or pharmaceutically acceptable salt thereof
UA101676C2 (uk) Піримідинові сполуки, композиції і способи застосування
ME02693B (fr) Dérivés de pyridinyl et triazolone pyridinyl de fusion
KR20190017030A (ko) Dnmt1의 억제제로서의 치환된 피리딘
AU2010249380A1 (en) N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[2,3-d]pyrimidines and pyrrol-3-yl-pyrrolo[2,3-d]pyrimidines as Janus kinase inhibitors
US20240124474A1 (en) Her2 mutation inhibitors
CN114945571B (zh) 环状化合物及其使用方法
BRPI0807165A2 (pt) Compostos de 2-amino pirimidina
AU2022265323C1 (en) Heterocyclic compounds capable of activating sting
CA3235913A1 (fr) Agents de degradation bifonctionnels de progeniteur hematopoietique kinase et leurs utilisations therapeutiques
AU2019295983B2 (en) Tricyclic compounds
WO2025019585A1 (fr) Inhibiteurs de kinases
WO2025031917A1 (fr) Dérivés de pipéridinylpyridinylcarbonitrile utilisés en tant qu'inhibiteurs de la glutaminyl-peptide cyclotransférase et de la protéine de type glutaminyl-peptide cyclotransférase
KR20210108433A (ko) 티에노피리디논 화합물

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24762447

Country of ref document: EP

Kind code of ref document: A1