Heterocyclic pericondensed CDC7 kinase inhibitors for the treatment of cancer
The present application relates to compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof. The present application also describes pharmaceutical composition comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for inhibiting kinase activity, and for treating cancer.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is a 5-10 membered heteroaryl, optionally substituted with 1-3 substituents independently selected from the group consisting of C1-C6 alkyl, amino, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, and C3-C6 cycloalkyl;
Y is —S— or —S(═O)—;
Ring A is a C5-C7 cycloalkyl or 5-7 membered heterocyclyl;
each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, —NR B R C , C1-C6 alkoxyalkyl, —C(═O) NH-5-10 membered heteroaryl, 4-6 membered heterocyclyl, 5-10 membered heteroaryl, C1-C6 alkyl optionally substituted with 1-3 independently selected R A , and C3-C6 cycloalkyl optionally substituted with hydroxyl; or
two R 2 together with the atom to which they are attached, join together to form an oxo group; a C3-C6 cycloalkyl optionally substituted with 1-3 substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy; or a 3-6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy;
R 3 is selected from hydrogen and C0-C6 alkyl optionally substituted with 1-4 substituents independently selected from:
(i) hydroxyl;
(ii) cyano;
(iii) halogen;
(iv) C3-C6 cycloalkoxy;
(v) C(═O) ORF;
(vi) C1-C6 alkoxy;
(vii) 4-10 membered heterocyclyloxy optionally substituted with 1-3 independently selected halogens;
(viii) —NR B R C ;
(ix) C3-C6 cycloalkyl optionally substituted with 1-3 groups independently selected from hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkoxy, —NR B R C , 3-6 membered heterocyclyloxy, and 3-6 membered heterocyclyl optionally substituted with 1-3 C 1 -C 6 alkoxy;
(x) 3 to 10 membered heterocyclyl optionally substituted with 1-4 substituents independently selected from halogen, hydroxyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkyl, —NR B R C , C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from halogen, C1-C6 alkoxy, and C3-C6 cycloalkoxy, and C3-C6 cycloalkyl optionally substituted with halogen or hydroxyl;
(xi) 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C3-C6 cycloalkyl, and 4-10 membered heterocyclyl, wherein said C3-C6 cycloalkyl is optionally substituted with 1-2 substituents independently selected from cyano and hydroxyl, and said 4-10 membered heterocyclyl is optionally substituted with 1-3 independently selected R A ; and
(xii) —C(═O)—X; wherein X is —NR B R C , C1-C6 alkyl, 5-6 membered heteroaryl, —NH-5-6 membered heteroaryl, —ORE, or 3-6 membered heterocyclyl optionally substituted with hydroxyl;
each R A and R E are independently halogen, cyano, hydroxyl, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkylamino, 4-6 membered heterocyclyl, or C3-C6 cycloalkyl;
each R B and R C are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, —C(═O)—C1-C6 alkyl, —(C1-C6 alkylene) p -C3-C8 cycloalkyl optionally substituted with C1-C6 alkyl, cyano, halogen, hydroxyl, or C3-C6 cycloalkyl; 3 to 6 membered heterocyclyl optionally substituted with C1-C6 alkyl; —C(═O)O—C1-C6 alkyl; or benzyl optionally substituted with C1-C6 alkoxy; or
R B and R C together with the atom to which they are attached, join together to form a 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, cyano, C1-C6 alkyl, —NR F R G , C3-C6 cycloalkoxy, C1-C6 haloalkoxy, and C1-C6 alkoxy;
each p is independently 0 or 1;
m is 0, 1, 2, 3, or 4;
R 4 is hydrogen or C1-C6 alkyl; and
each R F and R G are independently hydrogen or C1-C6 alkyl.
2 . The compound of claim 1 , wherein Y is —S—.
3 . The compound of claim 1 , wherein Ring A is a 5-7 membered heterocyclyl.
4 . The compound of claim 1 , wherein Ring A includes one oxygen atom.
5 . The compound of claim 1 , wherein:
a) R 1 is an unsubstituted 5-10 membered heteroaryl;
b) R 1 is an unsubstituted 5-6 membered heteroaryl;
c) R 1 is pyrazole;
d) R 1 is
e) R 1 is pyridine;
f) R 1 is
g) R 1 is pyrimidine; or
h) R 1 is
6 . The compound of claim 1 , wherein:
i) each R 2 is independently —C(═O)NH-5-10 membered heteroaryl;
j) each R 2 is independently 4-6 membered heterocyclyl;
k) each R 2 is independently 5-10 membered heteroaryl;
l) each R 2 is independently C3-C6 cycloalkyl optionally substituted with hydroxyl;
m) each R 2 is independently C1-C6 alkyl optionally substituted with 1-3 independently selected R A ; or
n) each R 2 is independently C1-C6 alkyl substituted with 1-3 independently selected R A .
7 . The compound of claim 1 , wherein two R 2 together with the atom to which they are attached, join together to form a 3-6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, cyano, C1-C6 alkyl, and C1-C6 alkoxy.
8 . The compound of claim 1 , wherein R 3 is C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 alkoxy, C3-C6 cycloalkoxy and C3-C6 cycloalkyl.
9 . The compound of claim 1 , wherein R 3 is C1-C6 alkyl substituted with azetidine, pyrrolidine or piperidine; each optionally substituted with C1-C6 alkyl, hydroxyl, or halogen.
10 . The compound of claim 1 , wherein R 3 is:
11 . The compound of claim 1 , wherein:
o) R 4 is C1-C6 alkyl;
p) R 4 is methyl; or
q) R 4 is hydrogen.
12 . A method for treating cancer in a subject in need thereof, comprising:
(a) determining if the cancer is associated with a dysregulation of a CDC7 gene, a CDC7 kinase, or expression or activity or level of any of the same; and
(b) if the cancer is determined to be associated with a dysregulation of a CDC7 gene, a CDC7 kinase, or expression or activity or level of any of the same, administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
13 . The method of claim 12 , wherein the step of determining if the cancer in the subject is a CDC7-associated cancer includes performing an assay to detect dysregulation in a CDC7 gene, a CDC7 kinase protein, or expression or activity or level of any of the same in a sample from the subject.
14 . The method of claim 12 , further comprising obtaining a sample from the subject.
15 . The method of claim 14 , wherein the sample is a biopsy sample.
16 . The method of claim 12 , further comprising administering an additional therapy or therapeutic agent to the subject.
17 . The method of claim 16 , wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted-therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies and angiogenesis-targeted therapies.
18 . The method of claim 16 , wherein the compound of claim 1 or a pharmaceutically acceptable salt or solvate thereof and the additional therapeutic agent are administered simultaneously as separate dosages.
19 . The method of claim 16 , wherein the compound of claim 1 or a pharmaceutically acceptable salt thereof and the additional therapeutic agent are administered as separate dosages sequentially in any order.
20 . A compound, wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.