Compounds and compositions for inhibition of FASN

Patent metadata

Field	Value
Publication number	US-10399951-B2
Application number	US-201816119962-A
Country	US
Kind code	B2
Filing date	Aug 31, 2018
Priority date	Mar 13, 2013
Publication date	Sep 3, 2019
Grant date	Sep 3, 2019

Abstract

The present invention relates to compounds and compositions for inhibition of FASN, their synthesis, applications, and antidotes.

First claim

The invention claimed is:

1. A fatty acid synthase inhibitor compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is a 5-membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of —R p , —OR p , —NHR p , and —NR p R p1 ,
or 3 or 4 membered cycloalkyl the 3 or 4 membered cycloalkyl is either unsubstituted or substituted with substituents selected from the group consisting of —R a , —OR a , —NHR a , and —NR a R a1 ;

L is a 6-membered monocyclic heteroalkyl wherein (i) the heteroatom ring members consist of two N, and (ii) 6-membered monocyclic heteroalkyl is substituted with one or more substituents selected from —R b ;
A and B are independently O or S;
Ar 1 is a 6-membered monocyclic aryl or heteroaryl substituted with one or more substituents selected from the group consisting of halo and C 1 -C 3 alkyl;
R 2 is a 4-15 membered monocyclic, bicyclic or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7 or 8 heteroatoms that are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl) 2 , —CH z F 3-z , —OCH z F 3-z , -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH 2 , —C(O)NH(alkyl), —C(O)N(aryl) 2 , —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO 2 ), —NH(SO 2 )alkyl, —NH(SO 2 )aryl, —NH(SO 2 )heteroaryl, —N(SO 2 )cycloalkyl, —C(O)N(alkyl) 2 , (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O) 2 -alkyl, —S(O) 2 -aryl, —S(O) 2 -cycloalkyl, —C(O)N(alkyl) 2 , —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R d , —NH—C(O)—R d —(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH 2 (CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R d )—C(O)-alkyl, —NH(R d )—C(O)-aryl, —NH(R d )—S(O 2 )cycloalkyl, —S(O 2 )NH 2 , —S(O 2 )NH(alkyl), —S(O 2 )N(R d )cycloalkyl, —S(O 2 )N(alkyl) 2 , —C(O)N(H)(alkyl), —C(O)N(R d )(cycloalkyl), methylenedioxy, —CH z F 3-z , —OCH z F 3-z , and -alkoxy;
R p and R p1 are independently H, halo, C 1 -C 4 alkyl, or C 3 -C 4 cycloalkyl;
R a and R a1 are independently H, halo, C 1 -C 4 alkyl, or C 3 -C 4 cycloalkyl;
R b is halo, C 1 -C 4 alkyl, C 1 -C 3 hydroxyl-alkyl, or C 3 -C 4 cycloalkyl;
R c is H, halo, C 1 -C 4 alkyl, or C 3 -C 4 cycloalkyl;
R d is H, halo, C 1 -C 4 alkyl, or C 3 -C 4 cycloalkyl;
and z is 0, 1 or 2.

2. The compound of claim 1 , wherein
(a) A and B are O; and
(b) R 1 is a 3 or 4 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of —R a , —OR a , —NHR a , and —NR a R a1 .

3. The compound of claim 2 , wherein R 2 is a substituted or unsubstituted monocyclic or bicyclic 5-10 membered aryl or heteroaryl.

4. The compound of claim 2 , wherein R 2 is a substituted or unsubstituted form of:

5. A fatty acid synthase inhibitor compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is a 3 or 4 membered cycloalkyl wherein the 3 or 4 membered cycloalkyl is either unsubstituted or substituted with substituents selected from the group consisting of —R a , —OR a , —NHR a , and —NR a R a1 ;
L is a

A and B are independently O or S;
Ar 1 is a 6-membered monocyclic aryl, heteroaryl or heterocycloalkyl, wherein (i) said 6-membered monocyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S or O, and (ii) each of said 6-membered monocyclic aryl, heteroaryl, or heterocycloalkyl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of halo, alkyl, —CH z F 3-z , cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl) 2 , —OCH z F 3-z , -alkyl, -alkenyl, -alkynyl, -alkoxy (alkoxyalkyl)amino-, —N(R c )—C(O)-alkyl, —N(R c )—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O;
R 2 is a 4-15 membered monocyclic, bicyclic or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7 or 8 heteroatoms that are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH 2 , —C(O)NH(alkyl), —C(O)N(alkyl) 2 , —C(O)NH(aryl), —C(O)N(aryl) 2 , —CH z F 3-z , —OCH z F 3-z , -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(cycloalkyl), —O(heterocycloalkyl), —O(heteroaryl), ONH 2 , —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO 2 ), —NH(SO 2 )alkyl, —NH(SO 2 )aryl, —NH(SO 2 )heteroaryl, —N(SO 2 )cycloalkyl, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O) 2 -alkyl, —S(O) 2 -aryl, —S(O) 2 -cycloalkyl, —C(O)alkyl, —NH—C(O)-alkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R d , —NH—C(O)—R d , —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH 2 (CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, —NH—C(O)—O-cycloalkyl, —N(R d )—C(O)-alkyl, —N(R d )—C(O)-aryl, —N (R d )—S(O 2 )cycloalkyl, —S(O 2 )NH 2 , —S(O 2 )NH(alkyl), —S(O 2 )N(R d )cycloalkyl, —S(O 2 )N(alkyl) 2 , —C(O)N(H)(alkyl), —C(O)N(R d )(cycloalkyl), and methylenedioxy;
R p and R p1 are independently H, halo, C 1 -C 4 alkyl, or C 3 -C 4 cycloalkyl;
R a and R a1 are independently H, halo, C 1 -C 4 alkyl, or C 3 -C 4 cycloalkyl;
R b is halo, C 1 -C 4 alkyl, C 1 -C 3 hydroxyl-alkyl, or

Assignees

• Forma Therapeutics Inc

Inventors

• Bair Kenneth W
• Lancia Jr David R
• Li Hongbin
• Loch James
• Lu Wei
• Martin Matthew W
• Millan David S
• Schiller Shawn E R
• Tebbe Mark J

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D213/65

  attached in position 3 or 5 · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D231/12

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D277/62

  Benzothiazoles · CPC title