Novel compounds and their use in therapy

Patent metadata

Field	Value
Publication number	US-2022411431-A1
Application number	US-202217874324-A
Country	US
Kind code	A1
Filing date	Jul 27, 2022
Priority date	Jun 29, 2015
Publication date	Dec 29, 2022
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 - 69 . (canceled)

70 . 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, Q and M are each nitrogen;
q is 0 or 1;
R 3 is hydrogen or methyl; R 4 is hydrogen or methyl;
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; 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 7 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 1-6 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.

71 . The inhibitor of NMT as claimed in claim 70 , 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—.

72 . The inhibitor of NMT as claimed in claim 70 , wherein the compound has the formula (IA)

73 . The inhibitor of NMT as claimed in claim 72 , 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.

74 . The inhibitor of NMT as claimed in claim 73 , wherein A is selected from the group consisting of substituted pyrazolyl and thiazolyl.

75 . The inhibitor of NMT as claimed in claim 74 , wherein A is substituted with 1, 2, or 3 groups, and at least one of the substituents is C(O)N(R 9 ) 2 .

76 . The inhibitor of NMT as claimed in claim 72 , 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 , —C(O)-1-pyrazole; and —C(O)-4-morpholine.

77 . The inhibitor of NMT as claimed in claim 70 , wherein q is 1, R 10 is hydrogen and R 11 is hydrogen.

78 . The inhibitor of NMT as claimed in claim 70 , 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.

79 . The inhibitor of NMT as claimed in claim 70 , wherein Y is —CH— or —C(R 2 )—.

80 . The inhibitor of NMT as claimed in claim 70 , wherein X is —O— and L is —(CH 2 ) m .

81 . The inhibitor of NMT as claimed in claim 70 , wherein R 7 is hydrogen or methyl, and/or R 7 is hydrogen or methyl.

82 . The inhibitor of NMT as claimed in claim 70 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.

83 . The inhibitor of NMT as claimed in claim 78 , wherein A is an optionally substituted 5-thiazolyl.

84 . The inhibitor of NMT as claimed in claim 83 , wherein the compound has the formula (IA″)

Assignees

• Imperial College Innovations Ltd

Inventors

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

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P33/06

  Antimalarials · CPC title

• C07D401/12

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

• C07D403/12

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