Lactam kinase inhibitors

Patent metadata

Field	Value
Publication number	US-9260442-B2
Application number	US-201414498796-A
Country	US
Kind code	B2
Filing date	Sep 26, 2014
Priority date	Mar 29, 2012
Publication date	Feb 16, 2016
Grant date	Feb 16, 2016

Abstract

Compounds useful as kinase inhibitors are provided herein, as well as salts, pharmaceutical compositions, methods of medical treatment and methods of synthesis thereof.

First claim

What is claimed is:

1. A compound of formula (Q):

wherein
R 26 is H, C 1 -C 6 alkyl, haloalkyl, cycloalkyl or heterocycloalkyl containing atoms selected from N, O, or S;
each R 31 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally substituted with N or O heteroatoms, and two R 31 s on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;
yy is 0, 1, 2, 3 or 4;
ZZ is —(CH 2 ) xx — wherein xx is 1, 2, 3, or 4, or —O—(CH 2 ) xx - wherein xx is 2, 3 or 4;
R 55 is NHR A , wherein R A is unsubstituted C 1 -C 8 alkyl, cycloalkylalkyl, -TT-RR, C 1 -C 8 cycloalkyl or heterocycloalkyl containing atoms selected from N, O, or S,
TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O, and S;
R 27 is -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroayl, -(alkylene) m -NR 3 R 4 , -(alkylene) m —C(O)—NR 3 R 4 , -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n—NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring,
providing that in (Q), R 27 may also be H, C 1 -C 3 alkyl or haloalkyl;
R 3 and R 4 at each occurrence are independently selected from:
(i) hydrogen, or
(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl, any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;
R x at each occurrence is independently selected from halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , (alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )-C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )-C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )-C(O)—R 5 , -(alkylene) m -N(R 3 )—(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 , -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:
said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)—R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *,
n is 0, 1 or 2, and
m is 0 or 1; and
R 3 * and R 4 * at each occurrence is independently selected from:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance; and
R 5 and R 5 * at each occurrence is independently selected from:
(i) hydrogen or
(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , having the formula:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein R 26 is selected from the group consisting of H, methyl, ethyl, n-propyl, cyclopropyl and sec-butyl.

5. The compound of claim 1 , wherein R 31 is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

6. The compound of claim 1 , wherein R 27 is selected from the group consisting of phenyl, ortho-methylphenyl, ortho, ortho-dimethylphenyl, para-ethylphenyl and ortho, para-dichlorophenyl.

7. The compound of claim 1 , wherein yy is 0, 1 or 2.

8. The compound of claim 1 , wherein R 3 and R 4 are independently selected from the group consisting of H, methyl, ethyl, and cyclohexyl.

9. The compound of claim 1 , wherein R 5 and R 5* are independently selected from the group consisting of H, methyl, ethyl, n-propyl and cyclopropylmethyl.

10. The compound of claim 1 , wherein R x is selected from the group consisting of chloro, methyl, ethyl and cyclopentyl.

11. The compound of claim 1 , wherein R 3* and R 4* are independently selected from the group consisting of H, methyl, ethyl, iso-propyl, n-buten-2-yl and phenyl.

12. The compound of claim 1 , wherein ZZ is selected from the group consisting of —CH 2 — and —CH 2 CH 2 —.

13. The compound of claim 1 , wherein R 55 is selected from the group consisting of cis 4-hydroxycyclohexylamino, trans 4-hydroxycyclohexylamino, cyclohexylamino, cyclopentylamino and straight chain C 1 -C 8 alkylamino.

Assignees

• G1 Therapeutics Inc

Inventors

• Tavares Francis Xavier

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D487/14 Primary

  Ortho-condensed systems · CPC title

• C07D498/14

  Ortho-condensed systems · CPC title

• C07D487/20

  Spiro-condensed systems · CPC title