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US 8,796,300 B2Granted
Therapeutic compounds
AssigneesRutgers, The State University of New Jersey, University of Medicine and Dentistry of New Jersey
InventorsEdmond J. LaVoie, Joseph E. Rice, Suzanne G. Rzuczek, Daniel S. Pilch
Life of this patent
Estimating the term…
Abstract
The invention provides compounds of formula (I) wherein u, d, v, m, n, R1, W, X, Y, and Z have any values defined herein, as well as salts thereof. The compounds have activity as anti-proliferative agents.
Claims16
A compound of formula (I):
- wherein:
- Z is CH or N;
- each W is independently NH, S, or O;
- n is 1 and m is 3;
- or n is 2 and m is 2;
- or n is 3 and m is 1;
- or n is 4 and m is 0;
- X is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of X is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- Y is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of Y is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- each R1 is independently H or (C1-C6)alkyl wherein any (C1-C6)alkyl of R1 is optionally is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyl oxy, (C1-C3)alkoxycarbonyl, —NRa1Rb1, —C(═O)NRa1Rb1, and —NRa1C(═O)—Rc1;
- each Ra and Rb is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra and Rb together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc is (C1-C3)haloalkyl;
- each Ra1 and Rb1 is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra1 and Rb1 together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc1 is halo(C1-C6)alkyl, (C1-C6)alkoxy or aryl(C1-C6)alkoxy;
- and
- wherein -u-d-v- is selected from:
- or a salt thereof.
18 more elements
A compound of formula Ia:
- wherein:
- X is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of X is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- Y is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa, Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of Y is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- Q is CH or N;
- R is CH or N;
- p is 0, 1, 2, 3, or 4;
- each Ra and Rb is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra and Rb together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc is (C1-C3)haloalkyl;
- and
- each Rd and Rc is independently H or (C1-C6)alkyl;
- or a salt thereof.
11 more elements
A compound of formula Ib:
- wherein:
- X is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of X is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- Y is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of Y is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- Q is CH or N;
- R is CH or N;
- p is 0, 1, 2, 3, or 4;
- each Ra and Rb is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra and Rb together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc is (C1-C3)haloalkyl;
- and
- each Rd and Re is independently H or (C1-C6)alkyl;
- or a salt thereof.
11 more elements
A compound of formula Ic:
- wherein:
- X is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of X is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- Y is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of Y is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- Q is CH or N;
- R is CH or N;
- p is 0, 1, 2, 3, or 4;
- each R1 is independently H or (C1-C6)alkyl wherein any (C1-C6)alkyl of R1 is optionally is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRa1Rb1, —C(═O)NRa1Rb1, and —NRa1C(═O)—Rc1;
- each Ra and Rb is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra and Rb together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc is (C1-C3)haloalkyl;
- each Rd and Re is independently H or (C1-C6)alkyl;
- each Ra1 and Rb1 is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra1 and Rb1 together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc1 is halo(C1-C6)alkyl, (C1-C6)alkoxy or aryl(C1-C6)alkoxy;
- and
- each Rz1 is independently H or (C1-C3)alkyl
- or a salt thereof.
16 more elements
A compound of formula Id:
- wherein:
- X is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of X is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, and —NRaC(═O)—Rc;
- Y is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of Y is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRa,Rb, and —NRaC(═O)—Rc;
- Q is CH or N;
- R is CH or N;
- p is 0, 1, 2, 3, or 4;
- each R1 is independently H or (C1-C6)alkyl wherein any (C1-C6)alkyl of R1 is optionally is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRa1Rb1, —C(═O)NRa1Rb1 and —NRa1C(═O)—Rc1;
- each Ra and Rb is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra and Rb together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc is (C1-C3)haloalkyl;
- each Rd and Re is independently H or (C1-C6)alkyl;
- each Ra1 and Rb1 is independently H, (C1-C6)alkyl, (C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra1 and Rb1 together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- each Rc1 is halo(C1-C6)alkyl, (C1-C6)alkoxy or aryl(C1-C6)alkoxy;
- and
- each Rz1 is independently H or (C1-C3)alkyl
- or a salt thereof.
16 more elements
A compound of formula Ie or formula If:
- wherein:
- X is H, hydroxy, halo, cyano, nitro, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, (C1-C6)alkoxycarbonyl, —NRaRb. —C(═O)NRaRb, or —NRaC(═O)—Rc;
- wherein each (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C1-C6)alkoxy, (C1-C6)alkanoyl, (C1-C6)alkanoyloxy, and (C1-C6)alkoxycarbonyl of X is optionally substituted with one or more groups independently selected from hydroxy, halo, cyano, nitro, (C1-C3)alkoxy, (C1-C3)alkanoyl, (C1-C3)alkanoyloxy, (C1-C3)alkoxycarbonyl, —NRaRb, —C(═O)NRaRb, and —NRaC(═O)—Rc;
- each Ra and Rb is independently H, (C(C1-C6)alkanoyl, or aryl(C1-C6)alkyl;
- or Ra and Rb together with the nitrogen to which they are attached form an N-linked heterocycle containing from 3 to 10 atoms that is optionally substituted with one or more oxo;
- and
- each Rc is (C1-C3)haloalkyl;
- or a salt thereof.
5 more elements
Dependencies are inferred from the claim text.