Compounds And Their Use As Inhibitors Of N-Myristoyl Transferase

Patent metadata

Field	Value
Publication number	US-2018370974-A1
Application number	US-201615739166-A
Country	US
Kind code	A1
Filing date	Jun 29, 2016
Priority date	Jun 29, 2015
Publication date	Dec 27, 2018
Grant date	—

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

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 1-4 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 independently nitrogen or C(R 7 );
K is carbon or nitrogen;
when K is carbon, either Q is N(R 8 ) and M is nitrogen or C(R 7 ), or Q is nitrogen and M is N(R 8 );
when K is nitrogen, Q is nitrogen or C(R 7 ) and M is nitrogen or C(R 7 );
and further wherein at least 2 of E, J, G, K, Q and M are selected from the group consisting of carbon and C(R 7 );
q is 0 or 1;
R 3 is hydrogen or methyl; R 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
R 8 is selected from the group selected from hydrogen and C 1-4 alkyl;
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 1-4 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 1-4 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 . An NMT 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 . An NMT inhibitor as claimed in claim 1 , wherein the compound has the formula (IA)

4 . An NMT inhibitor as claimed in claim 1 , wherein the compound has the formula (IB)

5 . An NMT inhibitor as claimed in claim 1 , wherein
i) E, J and G are each C(R 7 ), K is carbon, Q is N(R 8 ), and M is nitrogen; ii) E, J and G are each C(R 7 ), and K, Q and M are each nitrogen; iii) E and G are each C(R 7 ), and J, K, Q and M are each nitrogen; iv) J and G are each C(R 7 ), and E, K, Q and M are each nitrogen; or v) E, J, G and M are each C(R 7 ), and K and Q are each nitrogen.

6 . An NMT inhibitor as claimed in claim 1 , wherein q is 1, R 10 is hydrogen and R 11 is hydrogen, and K and Q are each nitrogen).

7 . An NMT 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 wherein the 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; —CH 2 C(O)N(R 9 ) 2 ; —C(O)N(R 13 )C 1-4 alkylOC 1-4 alkyl; —N(R 9 )C(O)C 1-4 alkyl, —CH 2 N(R 13 ) 2 , CH 2 N(R 9 )C(O)C 1-4 alkyl and CH 2 N(R 13 )S(O) 2 C 1-4 alkyl.

8 . An NMT inhibitor as claimed in claim 1 , wherein Y is —CH— or —C(R 2 ).

9 . An NMT inhibitor as claimed in claim 1 , wherein X is —O—; L is —(CH 2 ) m .

10 . An NMT inhibitor as claimed in claim 1 , wherein R 7 is hydrogen or methyl, and/or R 8 is hydrogen or methyl.

11 . An NMT inhibitor as claimed in claim 1 , wherein q is 1.

12 . An NMT 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 1 )S(O) 2 C 1-4 alkyl and CO 2 H.

13 . An NMT 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

Assignees

• Imperial Innovations Ltd

Inventors

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

Classifications

• A61P31/16

  for influenza or rhinoviruses · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D403/12

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

• C07D401/12

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