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WO2024182384A1 - Composés pyrrolidine et pyrrolidinone substitués - Google Patents

Composés pyrrolidine et pyrrolidinone substitués Download PDF

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Publication number
WO2024182384A1
WO2024182384A1 PCT/US2024/017466 US2024017466W WO2024182384A1 WO 2024182384 A1 WO2024182384 A1 WO 2024182384A1 US 2024017466 W US2024017466 W US 2024017466W WO 2024182384 A1 WO2024182384 A1 WO 2024182384A1
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alkyl
methyl
compound
pyrrolidine
halogen
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Kwon Ho Hong
Jean-Marc Lapierre
Yanbin Liu
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Cyteir Therapeutics Inc
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Cyteir Therapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Double-strand breaks are repaired by two major pathways: homologous recombination (HR) and non-homologous end- joining (NHEJ).
  • HR homologous recombination
  • NHEJ non-homologous end- joining
  • salt-EJ alternative end-joining
  • MMEJ microhomology-mediated end-joining pathway
  • DNA polymerase theta is an A-family polymerase encoded by the POLQ gene. It is a multi-functional protein that exhibits a C-terminal DNA polymerase domain (Pol ⁇ -pol), a central domain, and an N-terminal helicase domain (Pol ⁇ -hel). It is an error-prone polymerase that promotes MMEJ in higher organisms.
  • the Pol ⁇ -hel domain is a member of the SF2 helicases. While it has single-stranded DNA-dependent ATPase activity that can strip Replication Protein A (RPA) from single stranded DNA, it can suppress HR pathway by disrupting Rad51 nucleoprotein complex formation after radiation exposure.
  • RPA Replication Protein A
  • This anti- recombinase activity of Pol ⁇ promotes the alt-EJ pathway.
  • the helicase domain of Pol ⁇ can bridge two single stranded DNA sequences resulting in microhomology-mediated strand annealing. Specifically, Pol ⁇ promotes end-joining in alt- EJ pathway by employing this annealing activity even when single stranded DNA overhangs possess limited homology.
  • Pol ⁇ The Rad51 interaction is followed by ATPase-mediated displacement of Rad51 from DSB damage sites during the reannealing process. Once annealed, the primer strand of DNA is extended by the polymerase domain of Pol ⁇ . It has been shown that cancer cells with deficiency in HR, NHEJ or ataxia telangiectasia-mutated (ATM) are highly dependent on Pol ⁇ expression. Pol ⁇ has limited expression in normal cells, but is overexpressed in a variety of cancer cells. Depletion of Pol ⁇ can impair cell-viability and can lead to synthetic lethality of cancer cells. As such, Pol ⁇ is an attractive target for novel synthetic lethal therapy of cancers containing DNA repair defects. 1 298481291 Docket No.
  • CYTH-016/001WO 335739-2183 In view of the connection between the overexpression of Pol ⁇ in cancer cells, there is a need for compounds that inhibit Pol ⁇ polymerase activity.
  • the present disclosure addresses the need.
  • SUMMARY Disclosed herein are certain substituted pyrrolidine and pyrrolidinone compounds that inhibit DNA Polymerase Theta (Pol ⁇ ) activity, in particular inhibit the activity of the polymerase domain of Pol ⁇ .
  • described herein is a compound of Formula I: or a pharmaceutically acceptable salt or solvate thereof, wherein W, Y1, Y2, R1, R1’, R2, R2’, R5, R6, and R7 are described herein.
  • compositions comprising such compounds and methods of treating and/or preventing diseases, e.g., diseases such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • diseases e.g., diseases such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • a method for inhibiting DNA repair by Pol ⁇ in a cell comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the cell is HR deficient. 2 298481291 Docket No.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for inhibiting DNA repair by Pol ⁇ in a cell In some embodiments, the cell is HR deficient. In another aspect, described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • a disease in a subject e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Pol ⁇ in a cell.
  • the cell is HR deficient.
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject.
  • PARP poly(ADP-ribose) polymerase
  • cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer. 3 298481291 Docket No. CYTH-016/001WO 335739-2183 The details of the disclosure are set forth in the accompanying description below. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, illustrative methods and materials are now described. Other features, objects, and advantages of the disclosure will be apparent from the description and from the claims. In the specification and the appended claims, the singular forms also include the plural unless the context clearly dictates otherwise.
  • R 1 is halogen, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -NR a2 C(O)(C 1 -C 6 alkyl), -NR a2 C(O)O(C 1 -C 6 alkyl), or -NRa2C(O)NRa2(C1-C6 alkyl);
  • R1’ is H, C1-C6 alkyl, C1-C6 haloalkyl, or halogen; each R 2 is independently H, -OH, halogen, -NH 2 , or -NR a2
  • haloalkyl C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 ;
  • R4 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 halo
  • CYTH-016/001WO 335739-2183 wherein one or more hydrogen atoms in any of Ra1, Ra2, R1, R1’, R2, R2’, R3, R4, RN, RW, R5, R6, and R7 may be replaced with one or more deuterium atoms.
  • Various embodiments of the compounds of the present disclosure including embodiments of the various groups defined for any of W, X, Y1, Y2, RN, Ra1, Ra2, R1, R1’, R2, R2’, R3, R4, RW, R5, R6, and R7 are described herein, such as below.
  • any group or embodiment described herein for any of W, X, Y 1 , Y 2 , R N , R a1 , R a2 , R 1 , R 1 ’, R 2 , R 2 ’, R 3 , R 4 , R W , R 5 , R 6 , and R 7 can be combined with one or more groups or embodiments described herein for one or more of the remainder of W, X, Y1, Y2, RN, Ra1, Ra2, R1, R1’, R2, R 2 ’, R 3 , R 4 , R W , R 5 , R 6 , and R 7 .
  • a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, as described above.
  • Embodiment 2. The compound of Embodiment 1, of Formula II: or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment 3. The compound of Embodiment 1, of Formula IIIa or IIIb: or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment 4. The compound of Embodiment 1, of Formula IVa or IVb: 6 298481291 Docket No. CYTH-016/001WO 335739-2183 or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment 5. The compound of any of previous Embodiments to the extent applicable, wherein Y1 is O and Y2 is -NR3R4.
  • Embodiment 7 The compound of any of previous Embodiments to the extent applicable, wherein Y 1 and Y 2 , together with the carbon atom to which they are bonded, form .
  • Embodiment 7. The compound of any of previous Embodiments to the extent applicable, wherein W is N.
  • Embodiment 8 The compound of any of previous Embodiments to the extent applicable, wherein W is CR W .
  • R3 is C6-C10 aryl optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 10 The compound of any of previous Embodiments to the extent applicable, wherein R 3 phenyl optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 11 The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • R3 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 12a The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 12b The compound of any of previous Embodiments to the extent applicable, wherein R3 is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , - NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 12c The compound of any of previous Embodiments to the extent applicable, wherein R 3 is heteroaryl comprising one 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , - NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , - NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 12d The compound of any of previous Embodiments to the extent applicable, wherein R 3 is heteroaryl comprising two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 13 The compound of any of previous Embodiments to the extent applicable, wherein R 4 is H or C 1 -C 6 alkyl optionally substituted with one or more groups independently selected from C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 8 298481291 Docket No.
  • CYTH-016/001WO 335739-2183 alkyl -CN, halogen, C6-C10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 - C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, -NRa2C(X)ORa1, and - NR a2 C(X)NR a1 R a2 .
  • Embodiment 13a The compound of any of previous Embodiments to the extent applicable, wherein R4 is C1-C6 alkyl optionally substituted with one or more groups independently selected from C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, C 6 -C 10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -
  • Embodiment 13 The compound of any of previous Embodiments to the extent applicable, wherein R 4 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, optionally substituted with one or more groups independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, -OH, - NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, C 6 -C 10 aryl, and heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1- C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2
  • Embodiment 14 The compound of any of previous Embodiments to the extent applicable, wherein R 4 is C 6 -C 10 aryl, or heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and - NRa2C(
  • Embodiment 15 The compound of any of previous Embodiments to the extent applicable, wherein R 4 is C 6 -C 10 aryl, optionally substituted with one or more groups 9 298481291 Docket No. CYTH-016/001WO 335739-2183 independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 15a The compound of any of previous Embodiments to the extent applicable, wherein R4 is phenyl, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 16 The compound of any of previous Embodiments to the extent applicable, wherein R 4 is heteroaryl comprising one or two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 17 The compound of any of previous Embodiments to the extent applicable, wherein R 4 is heteroaryl comprising one 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, oxo, -C(X)R a1 , -C(X)OR a1 , -C(X)NR a1 R a2 , - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 17a The compound of any of previous Embodiments to the extent applicable, wherein R 4 is heteroaryl comprising one 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 17b The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising one 5-membered ring and 1-2 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , - NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, -NRa2C(X)Ra1, - NR a2 C(X)OR a1 , and -NR a2 C(X)NR a1 R a2 .
  • Embodiment 17d The compound of any of previous Embodiments to the extent applicable, wherein R4 is heteroaryl comprising two 5- or 6-membered rings and 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, oxo, -C(X)Ra1, -C(X)ORa1, -C(X)NRa1Ra2, - NRa2C(X)Ra1, -NRa2C(X)ORa1, and -NRa2C(X)NRa1Ra2.
  • Embodiment 18 The compound of any of previous Embodiments to the extent applicable, wherein R1’ is H and R1 is halogen, -NH2, -NRa2(C1-C6 alkyl), -NRa2C(O)(C1-C6 alkyl), -NRa2C(O)O(C1-C6 alkyl), or -NRa2C(O)NRa2(C1-C6 alkyl).
  • Embodiment 19 The compound of any of previous Embodiments to the extent applicable, wherein R 1 ’ is H and R 1 is halogen, -NH 2 , or -NR a2 (C 1 -C 6 alkyl).
  • Embodiment 20 The compound of any of previous Embodiments to the extent applicable, wherein R 1 ’ is H and R 1 is halogen, -NH 2 , or -NR a2 (C 1 -C 6 alkyl).
  • R 1 ’ is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen and R 1 is halogen, -NH 2 , - NR a2 (C 1 -C 6 alkyl), -NR a2 C(O)(C 1 -C 6 alkyl), -NR a2 C(O)O(C 1 -C 6 alkyl), or - NRa2C(O)NRa2(C1-C6 alkyl).
  • Embodiment 21 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen and R 1 is halogen, -NH 2 , - NR a2 (C 1 -C 6 alkyl), -NR a2 C(O)(C 1 -C 6 alkyl), -NR a2 C(O)O(C 1 -C 6 alkyl), or - NRa2C(O)NRa
  • RW is H.
  • Embodiment 24b The compound of any of previous Embodiments to the extent applicable, wherein R W is C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- 11 298481291 Docket No.
  • C1-C6 haloalkyl e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C 1 -C 6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy), or C1-C6 haloalkoxy (e.g., methoxy, ethoxy, propoxy, i- propoxy, n-butoxy, i-butoxy, s-butoxy, pentoxy, or hexoxy), or C1-C6 haloalkoxy (e.g., methoxy,
  • Embodiment 24c The compound of any of previous Embodiments to the extent applicable, wherein RW is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I).
  • RW is -OH, -NH2, -NRa2(C1-C6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl
  • Embodiment 25a The compound of any of previous Embodiments to the extent applicable, wherein R W is -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , or -NR a2 C(X)NR a1 R a2 .
  • Embodiment 25b The compound of any of previous Embodiments to the extent applicable, wherein R 5 , R 6 , and R 7 are each H.
  • Embodiment 25b The compound of any of previous Embodiments to the extent applicable, wherein R 5 , R 6 , and R 7 are each H.
  • R5, R6, and R7 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i- propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), C 1 -C 6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I), C1-C6 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy,
  • Embodiment 25c The compound of any of previous Embodiments to the extent applicable, wherein at least one of R 5 , R 6 , and R 7 is -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl) (wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl), -CN, or halogen (e.g., F, Cl, Br, or I). 12 298481291 Docket No. CYTH-016/001WO 335739-2183 Embodiment 25d.
  • halogen e.g., F, Cl, Br, or I
  • Embodiment 26a The compound of any of previous Embodiments to the extent applicable, wherein at least one of R 5 , R 6 , and R 7 is -NR a2 C(X)R a1 , -NR a2 C(X)OR a1 , or - NRa2C(X)NRa1Ra2.
  • Embodiment 26a The compound of any of previous Embodiments to the extent applicable, wherein R a1 is H.
  • Embodiment 26b The compound of any of previous Embodiments to the extent applicable, wherein R a1 is H.
  • Ra1 is C1-C6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s- butyl, t-butyl, pentyl, or hexyl), or C 1 -C 6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I
  • Embodiment 26c The compound of any of previous Embodiments to the extent applicable, wherein R a1 is C 1 -C 6 alkyl-C 6 -C 10 aryl, or C 1 -C 6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, - OH, -NH2, -NRa2(C1-C6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-
  • Embodiment 26d The compound of any of previous Embodiments to the extent applicable, wherein Ra1 is C1-C6 alkyl-C6-C10 aryl, wherein the aryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, and oxo, wherein the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl.
  • the alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl
  • Embodiment 26e The compound of any of previous Embodiments to the extent applicable, wherein R a1 is C 1 -C 6 alkyl-heteroaryl wherein the heteroaryl comprises a 5- or 6- membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the heteroaryl is optionally substituted with one or more groups independently selected from C1-C6 alkyl, C1- C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, -OH, -NH 2 , -NR a2 (C 1 -C 6 alkyl), -CN, halogen, 13 298481291 Docket No.
  • Embodiment 27a The compound of any of previous Embodiments to the extent applicable, wherein Ra2 is H.
  • R a2 is C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).
  • R a2 is C 1 -C 6 alkyl (e.g., methyl, ethyl, propyl, i-propyl, n- butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl).
  • Embodiment 28a The compound of any of previous Embodiments to the extent applicable, wherein X is O.
  • Embodiment 28b The compound of any of previous Embodiments to the extent applicable, wherein X is S.
  • Embodiment 28c The compound of any of previous Embodiments to the extent applicable, wherein X is NR N
  • Embodiment 29 The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C 1 -C 6 alkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl.
  • Embodiment 29a The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C 1 -C 6 alkyl is methyl, ethyl, propyl, or i-propyl.
  • Embodiment 30 The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C 1 -C 6 alkyl is methyl, ethyl, propyl, or i-propyl.
  • C 1 -C 6 haloalkyl is methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I.
  • C1-C6 haloalkyl is methyl, ethyl, propyl, or i-propyl, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • C1-C6 alkoxy is methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexoxy.
  • Embodiment 31a The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, C 1 -C 6 alkoxy is methoxy, ethoxy, propoxy, or i-propoxy.
  • C 1 -C 6 haloalkoxy is methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t- butoxy, pentoxy, or hexoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I.
  • C 1 -C 6 haloalkoxy is methoxy, ethoxy, propoxy, or i-propoxy, substituted with one or more halogen (e.g., F, Cl, Br, or I).
  • halogen e.g., F, Cl, Br, or I.
  • Embodiment 33 The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F, Cl, Br, or I.
  • Embodiment 33a The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is F.
  • Embodiment 33b The compound of any of previous Embodiments to the extent applicable, wherein in any of the groups defined for any of variables herein, as applicable, halogen is Cl.
  • non-limiting illustrative compounds of the present disclosure are listed in Table 1.
  • Table 1 Compounds of the Present Disclosure 15 298481291 Docket No. CYTH-016/001WO 335739-2183 16 298481291 Docket No. CYTH-016/001WO 335739-2183 17 298481291 Docket No. CYTH-016/001WO 335739-2183 18 298481291 Docket No. CYTH-016/001WO 335739-2183 19 298481291 Docket No.
  • a compound of the present disclosure is a pharmaceutically acceptable salt.
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • is a solvate is present in some embodiments.
  • a compound of the present disclosure e.g., a compound of any of the formulae or any individual compounds disclosed herein
  • the compounds of the present disclosure may form salts which are also within the scope of this disclosure.
  • Reference to a compound of the formulae herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salts include, e.g., water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, 20 298481291 Docket No.
  • CYTH-016/001WO 335739-2183 calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumerate, fiunarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate
  • Solidvate means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds or salts have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water, the solvate formed is a hydrate; and if the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one molecule of the substance in which the water retains its molecular state as H 2 O. Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement.
  • Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof.
  • the term “geometric isomer” refers to cyclic compounds having at least two substituents, wherein the two substituents are both on the same side of the ring (cis) or wherein the substituents are each on opposite sides of the ring (trans).
  • a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one or more of the possible stereoisomers, or geometric isomers, or a mixture of the encompassed stereoisomers or geometric isomers.
  • geometric isomer When a geometric isomer is depicted by name or structure, it is to be understood that the named or depicted isomer exists to a greater degree than another isomer, that is that the geometric isomeric purity of the named or depicted geometric isomer is greater than 50%, such as at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Geometric isomeric purity is determined by dividing the weight of the named or depicted geometric isomer in the mixture by the total weight of all of the geometric isomers in the mixture. 21 298481291 Docket No. CYTH-016/001WO 335739-2183 “Chiral isomer” means a compound with at least one chiral center.
  • a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center.
  • Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center.
  • the substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.1966, 5, 385; errata 511; Cahn et al., Angew.
  • the compounds of the disclosure are diastereomers.
  • the compounds are the syn diastereomer.
  • the compounds are the anti diastereomer. Racemic mixture means 50% of one enantiomer and 50% of is corresponding enantiomer.
  • Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent.
  • Enantiomers and diastereomers also can be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • a compound When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”).
  • Optical purity is the 22 298481291 Docket No. CYTH-016/001WO 335739-2183 weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.
  • stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is to be further understood that the stereoisomeric purity of the named or depicted stereoisomers at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. The stereoisomeric purity in this case is determined by dividing the total weight in the mixture of the stereoisomers encompassed by the name or structure by the total weight in the mixture of all of the stereoisomers.
  • Tautomer is one of two or more structural isomers that exist in equilibrium and is readily converted from one isomeric form to another. This conversion results in the formal migration of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a tautomeric set in solution. In solid form, usually one tautomer predominates. In solutions where tautomerization is possible, a chemical equilibrium of the tautomers will be reached. The exact ratio of the tautomers depends on several factors, including temperature, solvent and pH.
  • tautomerism The concept of tautomers that are interconvertable by tautomerizations is called tautomerism. Of the various types of tautomerism that are possible, two are commonly observed. In keto-enol tautomerism a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism arises as a result of the aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxy groups (-OH) in the same molecule to give it a cyclic (ring-shaped) form as exhibited by glucose.
  • -CHO aldehyde group
  • -OH hydroxy groups
  • Common tautomeric pairs are: ketone-enol, amide-nitrile, lactam- lactim, amide-imidic acid tautomerism in heterocyclic rings (e.g., in nucleobases such as guanine, thymine and cytosine), amine-enamine and enamine-imine.
  • the disclosure also comprehends isotopically-labeled compounds, which are identical to those recited in the each of the formulae described herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.
  • isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, fluorine, such as 3 H, 11 C, 14 C, 2 H and 18 F. 23 298481291 Docket No. CYTH-016/001WO 335739-2183 Compounds of the disclosure that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present disclosure. Isotopically-labeled compounds of the present disclosure, for example those into which radioactive isotopes such as 3 H, 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are useful for their ease of preparation and detectability.
  • 11 C and 18 F isotopes are useful in PET (positron emission tomography). PET is useful in brain imaging.
  • substitution with heavier isotopes such as deuterium, i.e., 2 H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
  • Isotopically labeled compounds of the disclosure can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples described herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. In some embodiments, the compounds of the disclosure are not isotopically labelled. Methods for Preparing the Compounds The compounds of the present disclosure may be made by a variety of methods, including standard chemistry. Suitable synthetic routes are depicted in the Schemes given below. The compounds may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic schemes.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles or chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.
  • the selection processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of the compounds of the present disclosure. Those skilled in the art will recognize if a stereocenter exists in the compounds of the present disclosure.
  • the present disclosure includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic compound but the individual enantiomers and/or diastereomers as well.
  • a compound When a compound is desired as a single 24 298481291 Docket No. CYTH-016/001WO 335739-2183 enantiomer or diastereomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994).
  • the compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes.
  • the compounds of the present disclosure can be prepared in a number of ways well known to those skilled in the art of organic synthesis.
  • the compounds of the present disclosure can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below.
  • the compounds of the present disclosure i.e., a compound of Formula I
  • alkyl refers to saturated, straight or branched-chain hydrocarbon radicals containing, In some embodiments, between one and six carbon atoms.
  • C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, n-heptyl, and n-octyl radicals. Examples of 25 298481291 Docket No.
  • C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, and n-hexyl radicals.
  • alkylsulfonyl means a -SO 2 R radical where R is alkyl as defined above, e.g., methylsulfonyl, ethylsulfonyl, 2-propylsulfonyl, and the like.
  • alkoxy means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl.
  • alkoxy includes methoxy, ethoxy, propoxy, and butoxy.
  • alkoxycarbonyl means a -COOR radical where R is alkyl as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, propoxy, or 2-propoxycarbonyl, or tertbutoxycarbonyl, and the like.
  • alkoxyalkyl means a linear monovalent hydrocarbon radical of one to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbons substituted with one alkoxy group, as defined above, e.g., 2-methoxyethyl, 1-, 2-, or 3- methoxypropyl, 2-ethoxyethyl, and the like.
  • acyl means a -C(O)R radical where R is alkyl as defined herein, e.g., methylcarbonyl, ethylcarbonyl, and the like.
  • acylamino means a -NHC(O)R radical where R is alkyl as defined herein, e.g., methylcarbonylamino, ethylcarbonylamino, and the like.
  • amino means a -NH 2 .
  • haloalkyl and haloalkoxy mean alkyl or alkoxy, as the case may be, substituted with one or more halogen atoms.
  • alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms unless otherwise stated e.g., methylene, ethylene, propylene, 1-methylpropylene, 2- methylpropylene, butylene, pentylene, and the like.
  • An “alkylene group” is a saturated aliphatic branched or straight-chain divalent hydrocarbon radical. Unless otherwise specified, an alkylene group typically has 1-6 carbon atoms, e.g., (C1-C6) alkylene.
  • aryl means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms e.g., phenyl or naphthyl.
  • Bicyclic heterocyclyl means a saturated monocyclic ring having 4 to 7 ring carbon ring atoms wherein one or two ring carbon atoms is(are) replaced by a heteroatom selected from N, O, or S(O) n, (where n is an integer from 0 to 2) that is fused to phenyl, five 26 298481291 Docket No. CYTH-016/001WO 335739-2183 or six-membered heteroaryl or heterocyclyl, each as defined herein.
  • Exemplary bicyclic heterocyclyl groups include, but are not limited to, and the like.
  • cycloalkyl means a monocyclic saturated hydrocarbon ring system.
  • C3-C7 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cycloheptyl.
  • a bridged cycloalkyl means a bicyclic hydrocarbon ring system in which the two rings share at least three adjacent ring carbon atoms.
  • a bridged cycloalkyl has 6- 12 ring carbon atoms.
  • Examples include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo [3.1.1]heptyl, and adamantyl.
  • heterocyclyl means saturated or unsaturated non-aromatic 4-10 membered ring radical containing from 1 to 4 ring heteroatoms, which may be the same or different, selected from N, O, or S. It can be monocyclic, bicyclic or tricyclic (e.g., a fused or bridged bicyclic or tricyclic ring).
  • Examples of include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.
  • a heterocyclic ring optionally contains one or more double bonds and/or is optionally fused with one or more aromatic rings (for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane).
  • aromatic rings for example, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, imidazopyrimidine, quinolinone, dioxaspirodecane.
  • 3-7 membered monocyclic heterocyclic ring examples include, but are not limited to, azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, tetrahydroimidazole, 27 298481291 Docket No.
  • CYTH-016/001WO 335739-2183 tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, and tetrahydrothiopyranyl.
  • bridged heterocyclyl means a saturated monocyclic ring having 5 to 7 ring carbon ring atoms in which two non-adjacent ring atoms are linked by a (CRR’)n group where n is 1 to 3 and each R and R’ is independently H or methyl (also may be referred to herein as “bridging” group) and further wherein one or two ring carbon atoms, including an atom in the bridging group, is replaced by a heteroatom selected from N, O, or S(O)n, where n is an integer from 0 to 2.
  • Bridged heterocyclyl is optionally substituted with one or two substituents independently selected from alkyl, halo, alkoxy, hydroxy, or cyano.
  • a bridged heterocyclyl means a bicyclic ring system containing from 1 to 4 ring heteroatoms in which the two rings share at least three adjacent ring atoms.
  • a bridged heterocyclyl has 6-12 ring atoms.
  • Examples include, but are not limited to, azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[3.2.1]octanyl, azabicyclo[2.2.1]heptany1, 2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3.0]nonanyl, and azabicyclo [3.3.1]nonanyl.
  • deuteroalkyl means an alkyl radical as defined above wherein one to six hydrogen atoms in the alkyl radical are replaced by deuterium, e.g., -CD 3 , -CH 2 CD 3 , and the like.
  • dialkylamino means -NRR’ radical where R and R’ are independently alkyl as defined herein.
  • halo means fluoro, chloro, bromo, or iodo, preferably fluoro or chloro.
  • heteroaryl when used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to aromatic ring groups having five to ten ring atoms selected from carbon and at least one (typically 1 to 4, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur).
  • Heteroaryl includes monocyclic rings and polycyclic rings in which a monocyclic heteroaromatic ring is fused to one or more other aromatic or heteroaromatic rings. “Heteroaryl” includes monocyclic and bicyclic ring systems. 28 298481291 Docket No. CYTH-016/001WO 335739-2183 “Monocyclic 5-6 membered heteroaromatic ring (or heteroaryl)” means a monocyclic heteroaromatic ring having five or six ring atoms selected from carbon and at least one (typically 1 to 3, more typically 1 or 2) heteroatoms (e.g., oxygen, nitrogen, or sulfur).
  • Examples of monocyclic 5-6 membered heteroaromatic ring groups include furanyl (e.g., 2- furanyl, 3-furanyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., 2-oxadiazolyl, 5- oxadiazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3- pyridyl
  • a non-hydrogen substituent replaces a hydrogen atom on a carbon or nitrogen.
  • a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen atom on the alkyl substituent.
  • monofluoroalkyl is alkyl substituted with a fluoro substituent
  • difluoroalkyl is alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).
  • the optional substituents can be any substituents that are suitable to attach to the moiety.
  • a person of ordinary skill in the art will recognize that the compounds and definitions provided do not include impermissible substituent patterns (e.g., methyl substituted with 5 different groups, and the like). Such impermissible substitution patterns are clearly recognized by a person of ordinary skill in the art.
  • a group is optionally substituted by 1-3 substituents.
  • Each R a’ and each R b’ are independently H or (C1 ⁇ C6) alkyl, wherein the (C1 ⁇ C6) alkyl group represented by R a’ or R b’ is optionally substituted, for example, with hydroxyl or (C1 ⁇ C3) alkoxy;
  • Suitable substituents may also include: -F, -Cl, -Br, -I, -OH, protected hydroxy, -NO2, -CN, -NH2, protected amino, -NH-C1-C12-alkyl, -NH-C2-C12-alkenyl, -NH-C2-C12-alkenyl, - NH -C 3 -C 12 -cycloalkyl, -NH-aryl, -NH -heteroaryl, -NH -heterocycloalkyl, -dialkylamino, - diarylamino, -diheteroarylamino, -O-C1-C12-alkyl, -O-C2-C12-alkenyl, -O-C2-C12-alkenyl, -O-C3-C12-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocycl
  • a "patient” or “subject” is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or rhesus.
  • An "effective amount” or “therapeutically effective amount” when used in connection with a compound or pharmaceutical composition is an amount effective for treating or preventing a disease in a subject as described herein. 31 298481291 Docket No. CYTH-016/001WO 335739-2183
  • the term "treating" with regard to a subject refers to improving at least one symptom of the subject's disorder.
  • Treating includes curing, improving, or at least partially ameliorating the disorder.
  • the compounds of the present disclosure, or a pharmaceutically acceptable salt or solvate thereof, can also be used to prevent a disease, condition or disorder.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
  • disorder is used in this disclosure to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
  • diseases or disorders in which Pol ⁇ polymerase plays a role means any disease or other deleterious condition in which Pol ⁇ polymerase is known to play a role.
  • compositions The compounds disclosed therein are Pol ⁇ polymerase inhibitors.
  • the pharmaceutical composition of the present disclosure comprises one or more Pol ⁇ polymerase inhibitors, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • a “pharmaceutical composition” is a formulation containing the compound of the present disclosure in a form suitable for administration to a subject. In some embodiments, the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient (e.g., a formulation of the disclosed compound or a pharmaceutically acceptable salt or solvate thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • active ingredient e.g., a formulation of the disclosed compound or a pharmaceutically acceptable salt or solvate thereof
  • the dosage will also depend on the route of administration.
  • routes including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this 32 298481291 Docket No. CYTH-016/001WO 335739-2183 disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers or propellants that are required.
  • the phrase “pharmaceutically acceptable” refers to those compounds, materials, compositions, carriers, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • “Pharmaceutically acceptable carrier” and “pharmaceutically acceptable diluent” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject.
  • Non-limiting examples of pharmaceutically acceptable carriers and/or diluents include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein.
  • auxiliary agents such
  • carrier encompasses carriers, excipients, and diluents and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ, or portion of the body of a subject.
  • the pharmaceutical compositions of the present teachings optionally include one or more pharmaceutically acceptable carriers and/or diluents therefor, such as lactose, starch, cellulose and dextrose.
  • excipients such as flavoring agents; sweeteners; and preservatives, such as methyl, ethyl, propyl and butyl parabens, can also be included. More 33 298481291 Docket No. CYTH-016/001WO 335739-2183 complete listings of suitable excipients can be found in the Handbook of Pharmaceutical Excipients (5 th Ed., Pharmaceutical Press (2005)). A person skilled in the art would know how to prepare formulations suitable for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington’s Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19) published in 1999.
  • compositions of the disclosure are formulated to be compatible with its intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous disclosure can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • the parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • a compound or pharmaceutical composition of the disclosure can be administered to a subject in many of the well-known methods currently used for chemotherapeutic treatment.
  • a compound of the disclosure may be injected directly into tumors, injected into the blood stream or body cavities or taken orally or applied through the skin with patches.
  • the dose chosen should be sufficient to constitute effective treatment but not as high as to cause unacceptable side effects.
  • the state of the disease condition e.g., cancer, precancer, and the like
  • the health of the patient should preferably be closely monitored during and for a reasonable period after treatment.
  • therapeutically effective amount refers to an amount of a pharmaceutical agent to treat, ameliorate, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect.
  • the effect can be detected by any assay 34 298481291 Docket No. CYTH-016/001WO 335739-2183 method known in the art.
  • the precise effective amount for a subject will depend upon the subject’s body weight, size, and health; the nature and extent of the condition; and the therapeutic or combination of therapeutics selected for administration. Therapeutically effective amounts for a given situation can be determined by routine experimentation that is within the skill and judgment of the clinician.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models, usually rats, mice, rabbits, dogs, or pigs.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD 50 (the dose lethal to 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • compositions that exhibit large therapeutic indices are preferred.
  • the dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • compositions containing active compound (i.e., a compound of Formula (I)) of the present disclosure may be manufactured in a manner that is generally known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or auxiliaries that facilitate processing of the active compound into preparations that can be used pharmaceutically. Of course, the appropriate formulation is dependent upon the route of administration chosen. 35 298481291 Docket No.
  • compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, Cremophor EL ⁇ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • Oral compositions generally include an inert diluent or an edible pharmaceutically acceptable carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically 36 298481291 Docket No.
  • the compound is delivered in the form of an aerosol spray from pressured container or dispenser, which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.
  • a suitable propellant e.g., a gas such as carbon dioxide, or a nebulizer.
  • Systemic administration can also be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compound is formulated into ointments, salves, gels, or creams as generally known in the art.
  • the active compound can be prepared with pharmaceutically acceptable carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No.4,522,811. It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage.
  • Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. 37 298481291 Docket No.
  • the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved.
  • the dosages of the pharmaceutical compositions used in accordance with the disclosure vary depending on the agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.
  • the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and also preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 5000 mg/kg per day.
  • an effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a subject may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped.
  • the term “dosage effective manner” refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • the pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the dosage regimen utilizing the compound is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or pharmaceutically acceptable salt or solvate thereof employed.
  • An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • Techniques for formulation and administration of the disclosed compound of the disclosure can be found in Remington: the Science and Practice of Pharmacy, 19 th edition, Mack Publishing Co., Easton, PA (1995).
  • the compound described herein, and the pharmaceutically acceptable salts or solvates thereof are used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent.
  • suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions.
  • the compound or pharmaceutically acceptable salts 38 298481291 Docket No. CYTH-016/001WO 335739-2183 or solvates thereof will be present in such pharmaceutical compositions in amounts sufficient to provide the desired dosage amount in the range described herein. All percentages and ratios used herein, unless otherwise indicated, are by weight. Other features and advantages of the present disclosure are apparent from the different examples. The provided examples illustrate different components and methodology useful in practicing the present disclosure.
  • the examples do not limit the claimed disclosure. Based on the present disclosure the skilled artisan can identify and employ other components and methodology useful for practicing the present disclosure. Methods of Using the Compounds The present disclosure provides a method of treating a subject with a disease or disorder which can be ameliorated by inhibition of Pol ⁇ polymerase or in which Pol ⁇ polymerase is involved, for example, in which the expression or activity of Pol ⁇ polymerase is dysregulated or aberrant, by administering to the subject an effective amount of one or more disclosed compounds, or a pharmaceutically acceptable salt or solvate thereof, or the corresponding pharmaceutical composition.
  • Diseases which can be ameliorated by inhibition of Pol ⁇ polymerase include cancer.
  • the present disclosure further relates to a method of treating a disease or disorder in which Pol ⁇ polymerase plays a role, for example, cancer.
  • the method comprises administering to a subject in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutical composition disclosed herein.
  • described herein is a method for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • described herein is a method for treating and/or preventing a cancer in a subject, such as cancer characterized by a deficiency in homologous recombinant (HR) or by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • HR homologous recombinant
  • BRCA gene expression the absence of the BRAC gene, or reduced function of BRCA protein
  • the cell is HR deficient.
  • the cell is HR deficient.
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for inhibiting DNA repair by Pol ⁇ in a cell.
  • the cell is HR deficient.
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, e.g., a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • a disease such as cancer treatable by inhibition of Pol ⁇ , including homologous recombination (HR) deficient cancers.
  • HR homologous recombination
  • described herein is a compound described herein or a pharmaceutically acceptable salt or solvate thereof for use in the manufacture of a medicament for treating and/or preventing a disease in a subject, such as cancer characterized by overexpression/overactivity of Pol ⁇ polymerase, by a deficiency in homologous recombinant (HR), or by a reduction or absence of BRAC gene expression, the absence of the BRAC gene, or reduced function of BRAC protein.
  • a compound described herein or a pharmaceutically acceptable salt or solvate thereof for treating and/or preventing a cancer that 40 298481291 Docket No.
  • CYTH-016/001WO 335739-2183 is resistant to poly(ADP-ribose) polymerase (PARP) inhibitor therapy in a subject.
  • PARP poly(ADP-ribose) polymerase
  • cancers resistant to PARP-inhibitors include, but are not limited to, breast cancer, ovarian cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, pancreatic cancer, gastrointestinal cancer, and colorectal cancer.
  • described herein is a method of treating cancer, the method comprising administering a therapeutically effective dose of a composition as described herein, e.g., a composition comprising a compound of the present disclosure, to a subject in need of treatment for cancer.
  • the present disclosure further relates to use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder in which Pol ⁇ polymerase plays a role, for example, a cancer.
  • the present disclosure provides use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a disease or disorder which can be ameliorated by inhibition of Pol ⁇ polymerase.
  • described herein is use of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment of a cancer.
  • the present disclosure further relates to a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder in which Pol ⁇ polymerase plays a role, for example, a cancer.
  • the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating a disease or disorder which can be ameliorated by inhibition of Pol ⁇ polymerase.
  • described herein is a method for treating and/or preventing a disease, such as cancer, characterized by overexpression of Pol ⁇ polymerase in a patient comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof.
  • a method for treating and/or preventing a homologous recombinant (HR) deficient cancer in a patient comprising administering to the 41 298481291 Docket No. CYTH-016/001WO 335739-2183 patient a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • HR homologous recombinant
  • described herein is a method for inhibiting DNA repair by Pol ⁇ in a cancer cell comprising contacting the cell with an effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof.
  • the cancer is HR deficient cancer.
  • described herein is a method for treating and/or preventing a cancer in a patient, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt or solvate thereof, optionally in a pharmaceutical composition.
  • the cancer is lymphoma, leukemia, multiple myeloma, soft tissue cancer, rhabdoid tumor, rhabdomyosarcoma, central nervous system cancer, peripheral nervous system cancer, bone cancer, uterine cancer, ovarian cancer, upper aerodigestive cancer, esophagus cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, mesothelioma, breast cancer, lung cancer, bladder cancer, liver cancer, head and neck cancer, fibroblast cancer, urinary tract cancer, kidney cancer, skin cancer, prostate cancer, and pancreatic cancer.
  • an HR-deficient cancer is breast cancer.
  • Breast cancer includes, but is not limited to, lobular carcinoma in situ (LCIS), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC), inflammatory breast cancer, Paget disease of the nipple, Phyllodes tumor, angiosarcoma, adenoid cystic carcinoma, low-grade adenosquamous carcinoma, medullary carcinoma, mucinous carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, micropapillary carcinoma, mixed carcinoma, and other breast cancer, including but not limited to, breast cancer that is triple negative, HER positive, estrogen receptor positive, progesterone receptor positive, HER and estrogen receptor positive, HER and progesterone receptor positive, estrogen and progesterone receptor positive, and/or HER and estrogen and progesterone receptor positive.
  • LCIS lobular carcinoma in situ
  • DCIS ductal carcinoma in situ
  • IDC invasive ductal carcinoma
  • inflammatory breast cancer Paget disease of the nipple
  • an HR-deficient cancer is ovarian cancer, including, but not limited to, epithelial ovarian carcinomas (EOC), maturing teratomas, dysgerminomas, endodermal sinus tumors, granulosa-theca tumors, Sertoli-Leydig cell tumors, and primary peritoneal carcinoma. 42 298481291 Docket No.
  • cancers that can be treated by the disclosed methods include cancer of the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; sarcomas; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chro
  • treating includes inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms; or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
  • inhibiting includes any measurable decrease or complete inhibition to achieve a desired result.
  • preventing refers to causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease.
  • homologous recombination refers to the cellular process of genetic recombination in which nucleotide sequences are exchanged between two similar or identical DNA.
  • homologous recombination (HR) deficient cancer refers to a cancer that is characterized by a reduction or absence of a functional HR repair pathway. HR deficiency may arise from absence of one or more HR-associated genes or presence of one or more mutations in one or more HR-associated genes.
  • HR-associated genes include BRCA1, BRCA2, RAD54, RAD51B, CtlP (Choline Transporter-Like Protein), PALB2 (Partner and Localizer of BRCA2), XRCC2 (X-ray repair complementing defective repair in Chinese hamster cells 2), RECQL4 (RecQ Protein-Like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome , one or more HR-associated genes) Nbs 1 (Nibrin), and genes encoding Fanconi anemia (FA) proteins or FA-like genes e.g., FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), FANCS (BRCA1), RAD51C, and XPF.
  • FANCA Fanconi anemia
  • Poly ⁇ ⁇ overexpression refers to the increased expression or activity of Pol ⁇ ⁇ in disease cells e.g., cancerous cell, relative to expression or activity of Pol ⁇ ⁇ in a normal cell (e.g., non-diseased cell of the same kind).
  • the amount of Pol ⁇ can be at least 2-fold, at least 3-fold, at least 4- fold, at least 5- fold, at least 10-fold, or more relative to the Pol ⁇ ⁇ expression in a normal cell.
  • Examples of Pol ⁇ ⁇ cancers include, but are not limited to, breast, ovarian, cervical, lung, colorectal, gastric, bladder and prostate cancers.
  • the compounds of the present disclosure can be co-administered with other therapeutic agents.
  • other therapeutic agents include chemotherapeutic agents known in the art, such as inhibitors of the DNA repair pathways (e.g., HR and NHEJ) and immunomodulatory agents.
  • chemotherapeutic agents known in the art, such as inhibitors of the DNA repair pathways (e.g., HR and NHEJ) and immunomodulatory agents.
  • co- administration is meant to encompass administration of two or more therapeutic agents to a single subject, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times.
  • These terms encompass administration of two or more agents to the subject so that both agents and/or their metabolites are present in the subject at the same time. They include simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present.
  • the compounds described herein and the other agent(s) are administered in a single composition.
  • the compounds described herein and the other agent(s) are admixed in the composition.
  • CYTH-016/001WO 335739-2183 To a solution of tert-butyl (2S,3S)-3-hydroxy-2-[methyl(m- tolyl)carbamoyl]pyrrolidine -1-carboxylate (1.00 g, 2.99 mmol) in THF (15 mL) was added PPh 3 (941 mg, 3.59 mmol,) and DIAD (726 mg, 3.59 mmol). The mixture was stirred at 20 °C for 30 min under N2. Then DPPA (988 mg, 3.59 mmol) was added and the mixture was stirred at 20 °C for 5 h under N2. The mixture was concentrated under reduced pressure.
  • CYTH-016/001WO 335739-2183 equiv) in DMF 100 mL was added TEA (11.8 g, 117 mmol, 3.0 equiv) and T3P (40.8 g, 64 mmol, 50.0% purity, 1.7 equiv).
  • TEA 11.8 g, 117 mmol, 3.0 equiv
  • T3P 40.8 g, 64 mmol, 50.0% purity, 1.7 equiv.
  • the mixture was stirred at 25 °C for 2 hrs, quenched by addition sat aq Na 2 CO 3 (500 mL) at 0 °C and extracted with EtOAc (300 mL*3).
  • CYTH-016/001WO 335739-2183 added CuI (4 mg, 23 ⁇ mol, 0.1 equiv), Pd(PPh3)4 (27 mg, 23 ⁇ mol, 0.1 equiv) and TEA (72 mg, 711 ⁇ mol, 3.0 equiv). The mixture was stirred at 60°C for 2 hrs under N2 atmosphere, quenched by H 2 O (5 mL) at 0 °C and extracted with EtOAc (10 mL * 3).
  • ESI [M+H] 412.2.
  • Polymerase theta polymerase domain activity assay Polymerase theta polymerase domain (amino acid residues 1819 to 2590) was expressed in E. coli as a hexahistidine fusion protein and purified by metal affinity chromatography. Polymerase activity was measured in 25 mM Tris•HCl (pH 7.5), 12.5 mM NaCl, 0.5 mM MgCl 2 , 0.01% Triton X-100, 0.1 mg/ml bovine gamma-globulin, 5% glycerol.
  • test compound dissolved in DMSO and DMSO were added to test wells to create a 9-point dilution series of test compound, no activity control wells, full activity control wells and a final DMSO volume of 100 nl.5 ⁇ l of assay buffer containing 40 nM polymerase domain was added to all wells except for no activity control wells, to which 5 ⁇ l of assay buffer was added.5 ⁇ l of assay buffer containing 20 ⁇ M each of dATP, dCTP, dGTP, dTTP and 200 nM primer (5’-GCGGCTGTCATAAG-3’)/template (5’- GCTACATTGACAATGGCATCAAATCTCAGATTGCGTCTTATGACAGCC GCG-3’) 110 298481291 Docket No.
  • CYTH-016/001WO 335739-2183 duplex (annealed at 20 ⁇ M in 20 mM Tris•HCl (pH 7.5), 50 mM NaCl) was added to all wells. Wells were covered and incubated at ambient temperature for 45 minutes.5 ⁇ l 25 mM Tris•HCl (pH 7.5),10 mM EDTA, 3.75% picogreen fluorescent DNA dye was added to all wells and incubated for 30 minutes prior to measuring fluorescence of each well at excitation wavelength 485nm and emission wavelength 528 nm. Inhibition of polymerase activity in test wells was calculated using no activity control well fluorescence as 100 % inhibition and full activity control wells as 0% inhibition.
  • Non-linear least squares fitting of inhibition as a function of inhibitor concentration was performed to determine maximum inhibition, minimum inhibition, IC 50 and Hill slope.
  • the biological activity of the compounds of the present application measured by the described assay above are shown in Table 2 below.
  • EQUIVALENTS The details of one or more embodiments of the disclosure are set forth in the accompanying description above.

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Abstract

La présente invention concerne des inhibiteurs de l'activité de l'ADN polymérase thêta (Polθ) représentés par la formule structurale suivante : (I), et leurs procédés d'utilisation, par exemple pour traiter le cancer.
PCT/US2024/017466 2023-02-28 2024-02-27 Composés pyrrolidine et pyrrolidinone substitués Ceased WO2024182384A1 (fr)

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WO2025011604A1 (fr) * 2023-07-13 2025-01-16 中国药科大学 INHIBITEUR DE POLθ ET SON PROCÉDÉ DE PRÉPARATION, COMPOSITION PHARMACEUTIQUE ET UTILISATION

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US20200129484A1 (en) * 2017-07-11 2020-04-30 Cyteir Therapeutics, Inc. Rad51 inhibitors
US20200181086A1 (en) * 2015-03-30 2020-06-11 Mission Therapeutics Limited 1-cyano-pyrrolidine compounds as usp30 inhibitors

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US20200181086A1 (en) * 2015-03-30 2020-06-11 Mission Therapeutics Limited 1-cyano-pyrrolidine compounds as usp30 inhibitors
US20200129484A1 (en) * 2017-07-11 2020-04-30 Cyteir Therapeutics, Inc. Rad51 inhibitors

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DATABASE PUBCHEM SUBSTANCE 2 June 2019 (2019-06-02), ANONYMOUS: "AKOS009167178", XP093209775, Database accession no. 145478441 *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025011604A1 (fr) * 2023-07-13 2025-01-16 中国药科大学 INHIBITEUR DE POLθ ET SON PROCÉDÉ DE PRÉPARATION, COMPOSITION PHARMACEUTIQUE ET UTILISATION

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