Compounds and their use as inhibitors of N-myristoyl transferase

Patent metadata

Field	Value
Publication number	US-11466011-B2
Application number	US-202016923133-A
Country	US
Kind code	B2
Filing date	Jul 8, 2020
Priority date	Jun 29, 2015
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

This invention provides compounds of formula (I) and salts thereof, which have activity as inhibitors of N-myristoyl transferase (NMT). The invention also relates to uses of such compounds as medicaments, in particular in the treatment of a disease or disorder in which inhibition of N-myristoyl transferase provides a therapeutic or prophylactic effect, including protozoan infections (such as malaria and leishmaniasis), viral infections (such as human rhinovirus and HIV), and hyperproliferative disorders (such as B-cell lymphoma).

First claim

The invention claimed is:

1. An inhibitor of N-myristoyl transferase (NMT) which is a compound of formula (I) or a salt thereof,

wherein:
Y is selected from the group consisting of —CH—, —C(R 2 )— and —N—;
R 1 is a group of formula —X-L-A;
X is selected from the group consisting of —O—, —N(H)— and —S—, or is absent;
L is selected from the group consisting of —(CHR 12 ) m — and —(CHR 12 ) m O—, or is absent;
m is 1, 2 or 3;
A is a 6-10-membered aromatic carbocycle or a 5-10-membered aromatic heterocycle, said aromatic carbocycle or heterocycle being optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of —F, —Cl, —Br, —OCH 3 , —OCF 3 , —CN, —C 1-6 alkyl optionally substituted by up to 3 halogen, hydroxyl, or —OC 1-4 alkyl groups, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —C(O)N(R 9 ) 2 , —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —CH 2 C(O)N(R 9 ) 2 , —CH 2 C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —CH 2 C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , —NHS(O) 2 C 1-4 alkyl, CH 2 N(R 13 ) 2 , CH 2 N(R 13 )C(O)C 1-4 alkyl, CH 2 N(R 13 )S(O) 2 C 1-4 alkyl, —CH 2 S(O) 2 C 1-4 alkyl, and CO 2 H;
s is 0, 1, 2, or 3;
each R 2 is independently selected from the group consisting of —F, —Cl, —Br, —OCH 3 , —OCF 3 , —CN, —C 1-4 alkyl optionally substituted by up to 3 halogen or hydroxyl groups, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , and —NHS(O) 2 C 1-4 alkyl;
E, J and G are each C(R 7 );
K is nitrogen;
Q is nitrogen and M is C(R 7 );
q is 0 or 1;
R 3 is hydrogen or methyl; R 4 is hydrogen or methyl;
R 5 is hydrogen or C 1-6 alkyl optionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH 3 , —OCF 3 or —CN groups; R 6 is hydrogen or C 1-6 alkyl optionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH 3 , —OCF 3 or —CN groups; or the R 5 and R 6 groups and the N they are bonded to form a 4 to 7 membered non-aromatic heterocycle, the heterocycle optionally comprising 1 or 2 further heteroatoms selected from N, O and S, optionally substituted by up to 3 —F, —Cl, —Br, —OH, —OCH 3 , —OCF 3 or —CN groups;
when present R 10 is hydrogen or methyl;
when present R 11 is hydrogen or methyl;
or the R 3 group and the R 5 group and the intervening atoms form a 3 to 7 membered non-aromatic heterocycle composed of the intervening atoms and bond, or the intervening atoms and —(CHR a ) r —; or the R 10 group and the R 5 group and the intervening atoms form a 3 to 7 membered non-aromatic heterocycle composed of the intervening atoms and —(CHR a ) r —;
r is 1, 2, 3, 4 or 5; R a is hydrogen or methyl;
each R 7 is independently selected from the group consisting of hydrogen, halogen, C 1-4 alkoxy, and C 1-4 alkyl optionally substituted with 1, 2 or 3 halogens; and
each R 9 is independently selected from the group consisting of hydrogen and C 1-4 alkyl, or two R 9 groups and the N they are bonded to form a 4 to 7 membered non-aromatic heterocycle, the heterocycle optionally comprising 1 or 2 further heteroatoms selected from N, O and S; and
each R 12 is independently selected from the group consisting of hydrogen, C 1-6 alkyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH 3 , —OCF 3 or —CN groups, C 1-6 alkenyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH 3 , —OCF 3 or —CN groups, and C 1-6 alkynyl optionally substituted by up to 3 —F, —Cl, —Br, I, —OH, —OCH 3 , —OCF 3 or —CN groups; and each R 13 is independently selected from the group consisting of hydrogen and C 1-4 alkyl.

2. The inhibitor as claimed in claim 1 , wherein X is selected from the group consisting of —O—, —N(H)— and —S—; and/or L is selected from the group consisting of —(CHR 12 ) m — and —(CHR 12 ) m O—.

3. The inhibitor as claimed in claim 1 , wherein the compound has the formula (IA)

4. The inhibitor as claimed in claim 3 , wherein
Y is —CH—;
X is —O—;
L is —(CH 2 ) m ;
m is 1 or 2;
A is an aromatic carbocycle or heterocycle selected from the group consisting of phenyl, pyridinyl, quinolinyl, imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is —C(O)N(R 9 ) 2 , —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —CH 2 C(O)N(R 9 ) 2 , —CH 2 C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —CH 2 C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , CH 2 N(R 13 )C(O)C 1-4 alkyl, CH 2 N(R 13 )S(O) 2 C 1-4 alkyl, or CO 2 H;
q is 1;
R 7 is hydrogen or methyl; and
R 10 is hydrogen and R 11 is hydrogen.

5. The inhibitor as claimed in claim 4 , wherein A is selected from the group consisting of substituted pyrazolyl and thiazolyl.

6. The inhibitor as claimed in claim 5 , wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is C(O)N(R 9 ) 2 .

7. The inhibitor as claimed in claim 3 , wherein q is 1, R 10 is hydrogen, R 11 is hydrogen, and A is 4-pyrazolyl, substituted by up to 3 groups independently selected from the group consisting of —C 1-4 alkyl, —CH 2 OC 1-4 alkyl, CF 2 H, CF 3 , —C(O)N(Me) 2 , and —C(O)-4-morpholine.

8. The inhibitor as claimed in claim 1 , wherein q is 1, R 10 is hydrogen and R 11 is hydrogen.

9. The inhibitor as claimed in claim 1 , wherein A is an aromatic carbocycle or heterocycle selected from the group consisting of phenyl, pyridinyl, quinolinyl, imidazolyl, benzimidazolyl, pyrazolyl, thiazolyl, 1,2,3-triazolyl and 1,2,4-triazolyl, said aromatic carbocycle or heterocycle being optionally substituted with 1, 2, or 3 groups independently selected from the group consisting of —C 1-4 alkyl, wherein each —C 1-4 alkyl is optionally substituted by up to 3 halogen, hydroxyl or —OC 1-4 alkyl groups; —C(O)N(R 9 ) 2 ; —CH 2 C(O)N(R 9 ) 2 ; —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl; —CH 2 N(R 13 ) 2 and CH 2 N(R 13 )S(O) 2 C 1-4 alkyl.

10. The inhibitor as claimed in claim 1 , wherein Y is —CH— or —C(R 2 )—.

11. The inhibitor as claimed in claim 1 , wherein X is —O— and L is —(CH 2 ) m .

12. The inhibitor as claimed in claim 1 , wherein R 7 is hydrogen or methyl.

13. The inhibitor as claimed in claim 1 , wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is —C(O)N(R 9 ) 2 , —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —CH 2 C(O)N(R 9 ) 2 , —CH 2 C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl, —CH 2 C(O)N(C 1-4 alkylOC 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —NHC(O)CF 3 , CH 2 N(R 13 )C(O)C 1-4 alkyl, CH 2 N(R 13 )S(O) 2 C 1-4 alkyl, or CO 2 H.

14. The inhibitor as claimed in claim 1 , wherein the compound has the formula (IA*)

wherein each R 2* is independently selected from the group consisting of —F, —Cl, —Br, —OCH 3 , —OCF 3 , —CN, —C 1-4 alkyl optionally substituted by up to 3 halogen or hydroxyl groups, —S(O)C 1-4 alkyl, —S(O) 2 C 1-4 alkyl, —S(O) 2 NHC 1-4 alkyl, —S(O) 2 N(C 1-4 alkyl) 2 , —NHC 1-4 a

Assignees

• Imperial College Innovations Ltd

Inventors

• Bell Andrew Simon
• Tate Edward William
• Leatherbarrow Robin John
• Hutton Jennie Ann
• Brannigan James Antony

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/18

  for HIV · CPC title

• A61P33/06

  Antimalarials · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D403/12

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