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US 2020/0048228 A1Published application
Alvocidib prodrugs and their use as protein kinase inhibitors
AssigneeTolero Pharmaceuticals, Inc.
InventorsAdam Siddiqui-Jain, Yusuke Sawayama, Wataru Hirose, Hitoshi Ban
Life of this patent
Estimating the term…
Abstract
Compounds having the following structure (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R1, R2 and R3 are as defined herein, and wherein at least one of R1, R2 and R3 is not H, are provided. Pharmaceutical compositions comprising the compounds and methods for use of the compounds for treating diseases associated with overexpression of a cyclin-dependent kinase (CDK) are also provided.
Claims24
A compound having the following structure (I):
- or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
- R1, R2 and R3 are independently hydrogen, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —P(═O)(ORe)(NRfRg), —P(═O)(ORh)(ORi), -(L 1)OP(═O)(ORh)(ORi), -(L1)xCH[P(═O)(ORh)(ORi)]2, -(L1)xCH[P(═O)(ORj)(NRkRl)]2, —P(═O)(NRmRn)(NRoRp) or —P(═O)RqRr, provided at least one of R1, R2 and R3 is not hydrogen;
- Ra, Rb, Re and Rj are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl, provided that Ra is optionally substituted C2-C12 alkyl, substituted C1-C12 alkyl or optionally substituted aryl when both of R1 and R2 are hydrogen;
- Rc and Rd are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rc and Rd are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rf and Rg are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rf and Rg are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rh and Ri are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rh and Ri are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rk and Rl are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rk and Rl are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rm and Rn are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rm and Rn are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Ro and Rp are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Ro and Rp are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rq and Rr are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rq and Rr are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- L1 is, at each occurrence, independently C1-C6 alkylene;
- x is, at each occurrence, independently 0 or 1,
- provided that the compound is not:
17 more elements
4-6. (canceled)
10-52. (canceled)
59-62. (canceled)
A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient, and a compound having the following structure (I):
- or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
- R1, R2 and R3 are independently hydrogen, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —P(═O)(ORe)(NRfRg), —P(═O)(ORh)(ORi), -(L1)OP(═O)(ORh)(ORi), -(L1)CH[P(═O)(ORh)(ORi)]2, -(L1)xCH[P(═O)(ORj)(NRkRl)]—P(═O)(NRmRn)(NRoRp) or —P(═O)RqRr, provided at least one of R1, R2 and R3 is not hydrogen;
- Ra, Rb, Re and Rf are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl, provided that Ra is optionally substituted C2-C12 alkyl, substituted C1-C12 alkyl or optionally substituted aryl when both of R1 and R2 are hydrogen;
- Rc and Rd are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rc and Rd are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rf and Rg are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rf and Rg are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rh and Ri are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rh and Ri are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rk and Rl are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rk and Ri are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rm and Rn are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rm and Rn are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Ro and RP are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Ro and RP are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rq and Rr are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rq and Rr are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- L1 is, at each occurrence, independently C1-C6 alkylene;
- x is, at each occurrence, independently 0 or 1,
- provided that the compound is not:
17 more elements
A method for treating a disease associated with overexpression of a cyclin-dependent kinase (CDK) in a mammal in need thereof, the method comprising administering a therapeutically effective amount of a compound having the following structure (I):
- or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:
- R1, R2 and R3 are independently hydrogen, —C(═O)Ra, —C(═O)ORb, —C(═O)NRcRd, —P(═O)(ORe)(NRfRg), —P(═O)(ORh)(ORi), -(L1)OP(═O)(ORh)(ORi), -(L1)XCH[P(═O)(ORh)(ORi)]2, -(L1)xCH[P(═O)(ORj)(NRkRl)]2, —P(═O)(NRmRn)(NRoRp) or —P(═O)RqRr, provided at least one of R1, R2 and R3 is not hydrogen;
- Ra, Rb, Re and Rf are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl, provided that Ra is optionally substituted C2-C12 alkyl, substituted C1-C12 alkyl or optionally substituted aryl when both of R1 and R2 are hydrogen;
- Re and Rd are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rc and Rd are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rf and Rg are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rf and Rg are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rh and Ri are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rh and Ri are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rk and Rl are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rk and Rl are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rm and Rn are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rm and Rn are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Ro and Rp are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Ro and Rp are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- Rq and Rr are, at each occurrence, independently hydrogen, optionally substituted C1-C12 alkyl or optionally substituted aryl;
- or Rq and Rr are taken together to form an optionally substituted 3- to 12-membered heterocyclic ring;
- L1 is, at each occurrence, independently C1-C6 alkylene;
- x is, at each occurrence, independently 0 or 1,
- provided that the compound is not:
17 more elements
69-70. (canceled)
Dependencies are inferred from the claim text.