MCL-1 inhibitors

Patent metadata

Field	Value
Publication number	US-10988451-B2
Application number	US-202016857021-A
Country	US
Kind code	B2
Filing date	Apr 23, 2020
Priority date	May 14, 2018
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

The present disclosure generally relates to compounds and pharmaceutical compositions that may be used in methods of treating cancer.

First claim

The invention claimed is:

1. A compound according to Formula (I):

wherein:
is a single or double bond;
X is O or NR 7 ;
R 12 is hydrogen or —C(O)R 1 ;
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-12 membered heterocyclyl, 5-10 membered heteroaryl, —OR 7 , or —NR 8 R 9 , wherein
said C 1-6 alkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-12 membered heterocyclyl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R 10 groups;

R 2 is hydrogen, C 1-6 alkyl, C 1-6 heteroalkyl, C 3-10 cycloalkyl, or 3-12 membered heterocyclyl, wherein
said C 1-6 alkyl, C 1-6 heteroalkyl, C 3-10 cycloalkyl, and 3-12 membered heterocyclyl are optionally substituted with 1-5 R 10 groups;

R 3 and R 4 are independently hydrogen, C 1-6 alkyl, —OR 7 , C 1-6 heteroalkyl, —NR 8 R 9 , NR 8 C(O)R 9 , —NRC(O)OR 9 , C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, —C(O)R 7 , —C(O)OR 7 , —C(O)NR 8 R 9 , —OC(O)NR 8 R 9 , —CN, or —SO 2 R 7 , wherein
said C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are optionally substituted with 1-5 R 10 groups;

R 5 is hydrogen, C 1-6 alkyl, —(CH 2 CH 2 O) p R 7 , C 1-6 heteroalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, wherein
said C 1-6 alkyl, C 1-6 heteroalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are optionally substituted with 1-5 R 10 groups;

R 6 is hydrogen or halo;
each R 7 is independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, wherein
said C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with from 1-5 R 10 ;

each R 8 and R 9 are independently hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, or 5-10 membered heteroaryl, or R 8 and R 9 together with the atoms to which they are attached form a 3-12 membered heterocycle, wherein
said C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl are optionally substituted with 1-5 R 10 ;

each R 10 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, halo, oxo, —OR a , —C(O)R a , —C(O)OR a , —C(O)NR a R b , —OC(O)NR a R b , —NR a R b , —NR a C(O)R b , —NR a C(O)OR b , —S(O) q R a , —S(O) 2 NR a R b , —NR a S(O) 2 R b , —N 3 , —CN, or —NO 2 , or two R 10 groups form a fused, spiro, or bridged C 3-10 cylcloalkyl or 3-12 membered heterocyclyl, wherein
each C 1-6 alkyl, C 1-6 heteroalkyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, 3-12 membered heterocycle, and 5-10 membered heteroaryl is optionally substituted with 1-5 R 20 groups;

each R a and R b is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, or R a and R b together with the atoms to which they are attached form a 3-12 membered heterocyclyl wherein
said C 1-6 alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl is optionally substituted with 1-5 R 20 groups;

each R 20 is independently C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 heteroalkyl, 3-12 membered heterocyclyl, C 6 -C 10 aryl, 5-10 membered heteroaryl, hydroxyl, C 1-6 alkoxy, amino, —CN, —C(O)H, —C(O)NH 2 , —C(O)NH(C 1-6 alkyl), —C(O)N(C 1-6 alkyl) 2 , —COOH, —C(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, or halogen;
n is 0, 1, or 2;
p is 0, 1, or 2;
q is 0, 1, or 2;
the C 1-6 heteroalkyl is an alkyl group in which one to three of the carbon atoms are each independently replaced with the same or different heteroatomic group; wherein C 1-6 heteroalkyl has 1-6 carbon atoms; and wherein the heteroatomic group is independently selected from nitrogen, sulfur, phosphorus, oxygen, —N(O)—, —S(O)—, and —S(O) 2 —;
the 3-12 membered heterocyclyl is a non-aromatic group having a single ring or multiple rings; wherein the 3-12 membered heterocyclyl has one to three heteroatoms independently selected from nitrogen, sulfur, phosphorus, —N(O)—, —S(O)—, and —S(O) 2 —; wherein the multiple rings may be fused, bridged, or spiro; and
the 5-10 membered heteroaryl is an aromatic group having a single ring or multiple rings; wherein the 5-10 membered heteroaryl contains one to three ring heteroatoms independently selected from nitrogen, oxygen, sulfur, —N(O)—, —S(O)—, and —S(O) 2 ;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , according to Formula (IIIb):

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is 5-10 membered heteroaryl containing 1-2 heteroatoms; wherein each heteroatom is independently selected from nitrogen, sulfur, and oxygen; wherein
the 5-10 membered heteroaryl of R 1 is optionally substituted with 1-3 substituents independently selected from halo, hydroxyl, —CN, C 1-6 alkyl, C 1-6 haloalkyl, —OR a , and C 3-6 cycloalkyl; and
each R 2 , R 3 , R 4 , and R 5 is independently hydrogen or C 1-6 alkyl;
R 6 is hydrogen or halo; and
R a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, and C 3-10 cycloalkyl.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, according to Formula (IIIc):

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, according to Formula (IIId):

5. The compound of claim 1 , wherein:
R 3 is C 1-3 alkyl;

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is Cl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

substituted with 1-2 R 10 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

substituted with two groups selected from C 1-4 alkyl and C 1-4 alkoxyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:

Assignees

• Gilead Sciences Inc

Inventors

• Chu Hang
• Guerrero Juan A
• Hurtley Anna E
• Hwang Tae H
• Jiang Lan
• Kato Darryl
• Kobayashi Tetsuya
• Knox John E
• Lazerwith Scott E
• Li Xiaofen
• Lin David W
• Medley Jonathan W
• Mitchell Michael L
• Naduthambi Devan
• Newby Zachary
• Squires Neil H
• Tsui Vickie H
• Venkataramani Chandrasekar
• Watkins William J
• Yang Hong

Classifications

• C07D513/08 Primary

  Bridged systems · CPC title

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title