Inhibiting fatty acid synthase (FASN)

Patent metadata

Field	Value
Publication number	US-10875848-B2
Application number	US-201916598481-A
Country	US
Kind code	B2
Filing date	Oct 10, 2019
Priority date	Oct 10, 2018
Publication date	Dec 29, 2020
Grant date	Dec 29, 2020

Abstract

The present disclosure is directed to inhibitors of FASN. The compounds can be useful in the treatment of disease or disorders associated with the inhibition of FASN. For instance, the disclosure is concerned with compounds and compositions for inhibition of FASN, methods of treating, preventing, or ameliorating diseases or disorders associated with the inhibition of FASN, and methods of synthesis of these compounds.

First claim

We claim:

1. A compound of Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is 6-10 membered aryl or 6-10 membered heteroaryl containing 1-2 N atoms;
R 1 is C 1-3 aliphatic, 3-4 membered cycloalkyl, 5-membered heterocyclyl containing 1 O atom, or 5-membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O and N,
wherein R 1 is optionally substituted with —OH or —NH 2 ;

R 2 is —CO 2 R 3 , —SO 2 NHCOR 3 , or an optionally substituted group selected from the group consisting of 3-4 membered cycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S, wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d ;
each R a is independently halogen;
each R b is independently C 1-3 aliphatic;
R c is hydrogen or halogen;
R c′ is hydrogen or halogen;
R c″ is hydrogen, halogen, —CO 2 H, or tetrazole;
each R d is independently halogen, —CO 2 R 3 , —OR 3 , —S(O) 2 NH 2 , —SO 2 NHCOR 3 , —P(O)R 4 OR 3 , —CH 2 CO 2 R 3 , or an optionally substituted group selected from the group consisting of C 1-3 aliphatic, 4-membered cycloalkyl, and 5-membered heteroaryl containing 1-4 N atoms;
wherein an optionally substituted group of R d is optionally substituted with halogen, oxo, OH, or C 1-3 aliphatic;

each R 3 is independently hydrogen or C 1-3 alkyl optionally substituted with fluoro;
R 4 is C 1-6 aliphatic;
m is 0-4; and
n is 0-6.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,
wherein the compound is:

9. The compound of claim 1 , wherein the compound is selected from the group consisting of 4-{4-[(1S)-6-(1-hydroxycyclopropanecarbonyl)-6-azaspiro[2.5]octan-1-yl]phenyl}-3-methylbenzoic acid; (S)-4′-(6-(1-hydroxycyclopropane-1-carbonyl)-6-azaspiro[2.5]octan-1-yl)-6-methyl-[1,1′-biphenyl]-3-carboxylic acid; ((S)-1-(4′-(2H-tetrazol-5-yl)-[1,1′-biphenyl]-4-yl)-6-azaspiro[2.5]octan-6-yl)((R)-tetrahydrofuran-2-yl)methanone; 6-methoxy-4′-((S)-6-((R)-tetrahydrofuran-2-carbonyl)-6-azaspiro[2.5]octan-1-yl)-[1,1′-biphenyl]-3-carboxylic acid; 5-chloro-6-methoxy-4′-((S)-6-((R)-tetrahydrofuran-2-carbonyl)-6-azaspiro[2.5]octan-1-yl)-[1,1′-biphenyl]-3-carboxylic acid; ((S)-1-(2′-methoxy-4′-(2H-tetrazol-5-yl)-1′,2′,3′,4′,5′,6′-hexahydro-[1,1′-biphenyl]-4-yl)-6-azaspiro[2.5]octan-6-yl)((R)-tetrahydrofuran-2-yl)methanone; and 4-[4-[(1S)-6-(1-hydroxycyclopropanecarbonyl)-6-azaspiro[2.5]octan-1-yl]phenyl]quinoline-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is:

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

12. The compound of claim 1 , wherein R 2 is an optionally substituted group selected from the group consisting of 3-4 membered cycloalkyl, phenyl, and 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S; and wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d .

13. The compound of claim 12 , wherein each R d is independently halogen, —CO 2 R 3 , —OR 3 , —S(O) 2 NH 2 , —SO 2 NHCOR 3 , —P(O)R 4 OR 3 , or an optionally substituted group selected from the group consisting of C 1-3 aliphatic, or 5-membered heteroaryl containing 1-4 N atoms; wherein an optionally substituted group of R d is optionally substituted with halogen or C 1-3 aliphatic.

14. A compound of Formula (II)

or a pharmaceutically acceptable salt thereof, wherein:
Ring A is 6-10 membered aryl or 5-10 membered heteroaryl containing 1-2 heteroatoms independently selected from the group consisting of O, N, and S;
R 1 is C 1-6 aliphatic, 3-6 membered cycloalkyl, 4-6-membered heterocyclyl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S, or 5-6 membered heteroaryl containing 1-3 heteroatoms independently selected from the group consisting of O, N, and S; wherein R 1 is optionally substituted with halogen, oxo, —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ),—C(O)N(R 4 )(R 4′ ),—S(O) 2 N(R 4 )(R 4′ ), tetrazolyl, or C 1-3 alkyl optionally substituted with halogen or —CO 2 R 3 ;
R 2 is —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ),—C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), or an optionally substituted group selected from the group consisting of 3-7 membered cycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein an optionally substituted group of R 2 is optionally substituted with 1-6 R d ;
each R a is independently halogen, —CN, —NO 2 , —OR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ ), —SR 3 , —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), tetrazolyl, or C 1-3 aliphatic optionally substituted with halogen;
each R b is independently C 1-6 aliphatic optionally substituted with halogen;
R c is hydrogen or halogen;
R c′ is hydrogen or halogen;
each R d is independently halogen, oxo, —CN, —NO 2 , —OR 3 , —SR 3 , —CO 2 R 3 , —N(R 4 )(R 4′ )N(R 4 )(R 4′ ), —C(O)N(R 4 )(R 4′ ), —S(O) 2 N(R 4 )(R 4′ ), —COR 5 , —N(R 4 )COR 5 , —N(R 4 )SOR 5 , —N(R 4 )SO 2 R 5 , —SOR 5 , —SO 2R 5 , —N(R 4 )CO 2 R 3 , —N(R 4 )C(O)N(R 4 )(R 4′ ), or an optionally substituted group selected from the group consisting of C 1-6 aliphatic and 5-10 membered heteroaryl containing 1-4 heteroatoms independently selected from the group consisting of O, N, and S; wherein an optionally substituted group of R d is optionally substituted with halogen, —OH, —NH 2 , —CN, oxo, or C 1-3 alkyl;
each R 3 is independently hydrogen or C 1-6 aliphatic optionally substituted with halogen, —OH, —NH 2 , —CN, or oxo;
each R 4 is independently hydroge

Assignees

• Forma Therapeutics Inc

Inventors

• Martin Matthew W
• Zablocki Mary-Margaret
• Mente Scot
• Dinsmore Christopher
• Wang Zhongguo
• Zheng Xiaozhang

Classifications

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D221/20 Primary

  Spiro-condensed ring systems · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title