Phenol compound or salt thereof
The present invention provides a phenol compound represented by the following Formula (I) or a salt thereof: wherein R 1 , R 2 , R 5 , L 1 , L 2 , L 3 , A, X, and m are as described in the specification.
1 . A phenol compound represented by the following Formula (I) or a salt thereof:
wherein
R 1 represents substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted silyl, or substituted or unsubstituted sulfanyl;
R 2 represents halogen, cyano, nitro, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;
at least one of R 2 is present in the para-position of L 1 ,
m represents 1 or 2;
when m is 2, R 2 may be identical or different;
R 1 , and R 2 which is present in the para-position of L 1 , taken together with the following adjacent group:
may form
wherein
may have at least one member selected from the group consisting of halogen and C1-C6 alkyl as a substituent; and
z represents an integer of 1 to 3;
X represents nitrogen, CH, or CR 2 ;
L 1 represents —NH—C(Ra) 2 —, —C(Ra) 2 —, or —C(Ra) 2 —C(Ra) 2 —;
Ra are identical or different, and each represents hydrogen, C1-C6 alkyl, or hydroxyl;
ring A represents a 5- or 6-membered unsaturated heterocyclic group that may have substituent R 6 or a benzene ring that may have substituent R 6 ;
R 6 represents at least one member selected from the group consisting of halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl that may have substituent R 71 , C2-C6 alkenyl that may have substituent R 72 , C2-C6 alkynyl that may have substituent R 73 , C3-C10 cycloalkyl that may have substituent R 74 , C4-C10 cycloalkenyl that may have substituent R 75 , C6-C10 aromatic hydrocarbon that may have substituent R 76 , a 4- to 10-membered saturated heterocyclic group that may have substituent R 77 , and a 5- to 10-membered unsaturated heterocyclic group that may have substituent R 78 ; and when one or more substituents are present, they may be identical or different;
when R 6 is C1-C6 alkyl that may have substituent R 71 , C2-C6 alkenyl that may have substituent R 72 , or C2-C6 alkynyl that may have substituent R 73 , the substituent R 71 , R 72 , or R 73 represents halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkoxy, di(C1-C6 alkyl)amino, C3-C7 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated heterocyclic group; and when one or more substituents R 71 , R 72 , or R 73 are present, they may be identical or different;
when R 6 is C3-C10 cycloalkyl that may have substituent R 74 , C4-C10 cycloalkenyl that may have substituent R 75 , C6-C10 aromatic hydrocarbon that may have substituent R 76 , a 4- to 10-membered saturated heterocyclic group that may have substituent R 77 , or a 5- to 10-membered unsaturated heterocyclic group that may have substituent R 78 , the substituent R 74 , R 75 , R 76 , R 77 , or R 78 represents halogen, cyano, nitro, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, di(C1-C6 alkyl)amino, (C1-C6 alkyl) carbonyl, C7-C14 aralkyl, (C1-C6 alkoxy) carbonyl, C3-C7 cycloalkyl, C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated heterocyclic group; and when one or more substituents R 74 , R 75 , R 76 , R 77 , or R 78 are present, they may be identical or different;
L 2 represents
wherein
represents a 4- to 8-membered saturated heterocyclic ring having at least one nitrogen;
R 3 represents hydrogen or C1-C6 alkyl,
R 4 represents halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkyl that may have substituent R 8 , C2-C6 alkenyl, C2-C6 alkynyl, or C1-C6 alkoxy; when two R 4 are present on the same carbon atom, the two R 4 , taken together with the carbon atom to which these groups are attached, may form a 3- to 8-membered saturated hydrocarbon ring;
R 8 represents halogen, cyano, hydroxyl, C1-C6 alkoxy, or di(C1-C6 alkyl)amino;
n represents an integer of 0 to 3; and
when n is 2 or 3, R 4 may be identical or different;
L 3 represents —C(═O)— or —S(═O) 2 —; and
R 5 represents substituted or unsubstituted C2-C6 alkenyl or substituted or unsubstituted C2-C6 alkynyl.
2 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I),
R 1 represents substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C3-C7 cycloalkyl, tri (C1-C6 alkyl) silyl, or pentafluorosulfanyl,
when R 1 is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, or substituted or unsubstituted C3-C7 cycloalkyl, the substituent is halogen, cyano, or C1-C6 alkyl; and when one or more substituents are present, they may be identical or different,
R 2 represents halogen, cyano, C1-C6 alkyl, or C2-C6 alkenyl,
R 1 , and R 2 which is present in the para-position of L 1 , taken together with the following adjacent group:
may form
wherein
may have at least one member selected from the group consisting of halogen and C1-C6 alkyl as a substituent,
m represents 1 or 2,
z represents an integer of 1 to 3, and
X represents nitrogen or CH.
3 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I),
L 1 represents —NH—C(Ra) 2 —, —C(Ra) 2 —, or —C(Ra) 2 —C(Ra) 2 —, and
Ra are identical or different, and each represents hydrogen, methyl, or hydroxyl.
4 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I),
ring A represents
wherein
represents a single bond or a double bond,
A 1 represents C—Rb1, nitrogen, N—Rb1, oxygen, or sulfur,
A 2 represents C—Rb2, nitrogen, N—Rb2, oxygen, or sulfur,
A 3 represents C—Rb3, nitrogen, N—Rb3, oxygen, or sulfur,
A 4 represents carbon or nitrogen,
at least one of A 1 , A 2 , A 3 , and A 4 is at least one member selected from the group consisting of nitrogen, N—Rb1, N—Rb2, N—Rb3, oxygen, and sulfur,
A 5 represents C—Rb5 or N—Rb5, and at least one of A 5 is N—Rb5,
Rb1, Rb2, and Rb3 are identical or different, and each represents hydrogen, halogen, cyano, C1-C6 alkyl that may have substituent R 71 , alkenyl that may have substituent R 72 , alkynyl that may have substituent R 73 , C3-C7 cycloalkyl that may have substituent R 74 , C4-C7 cycloalkenyl that may have substituent R 75 , C6-C10 aromatic hydrocarbon that may have substituent R 76 , a 4- to 10-membered saturated heterocyclic group that may have substituent R 77 , or a 5- to 10-membered unsaturated heterocyclic group that may have substituent R 78 , when Rb1, Rb2, or Rb3 is C1-C6 alkyl that may have substituent R 71 , C2-C6 alkenyl that may have substituent R 72 , or C2-C6 alkynyl that may have substituent R 73 , the substituent R 71 , R 72 , or R 73 represents halogen, cyano, nitro, amino, hydroxyl, carboxyl, C1-C6 alkoxy, di(C1-C6 alkyl)amino, C3-C7 cycloalkyl, substituted or unsubstituted C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated heterocyclic group; and when one or more substituents R 71 , R 72 , or R 73 are present, they may be identical or different,
when Rb1, Rb2, or Rb3 is C3-C10 cycloalkyl that may have substituent R 74 , C4-C10 cycloalkenyl that may have substituent R 75 , C6-C10 aromatic hydrocarbon that may have substituent R 76 , a 4- to 10-membered saturated heterocyclic group that may have substituent R 77 , or a 5- to 10-membered unsaturated heterocyclic group that may have substituent R 78 , the substituent R 74 , R 75 , R 76 , R 77 , or R 78 represents halogen, cyano, nitro, amino, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, di(C1-C6 alkyl)amino, (C1-C6 alkyl) carbonyl, C7-C14 aralkyl, (C1-C6 alkoxy) carbonyl, C3-C7 cycloalkyl, C6-C10 aromatic hydrocarbon, a substituted or unsubstituted 4- to 10-membered saturated heterocyclic group, or a substituted or unsubstituted 5- to 10-membered unsaturated heterocyclic group; and when one or more substituents R 74 , R 75 , R 76 , R 77 , or R 78 are present, they may be identical or different,
Rb5 are identical or different, and each represents hydrogen, halogen, or C1-C6 alkyl, and
Rc are identical or different, and each represents hydrogen, halogen, or C1-C6 alkyl.
5 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I),
L 2 represents
wherein
represents azetidine or pyrrolidine, and
R 3 represents hydrogen or C1-C6 alkyl.
6 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I), L 3 represents —C(═O)—.
7 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I), R 5 represents vinyl, dimethylamino-1-propenyl, or 1-propynyl.
8 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I),
ring A represents
wherein
represents a single bond or a double bond,
A 1 represents C—Rb1, nitrogen, N—Rb1, oxygen, or sulfur,
A 2 represents C—Rb2, nitrogen, N—Rb2, oxygen, or sulfur,
A 3 represents C—Rb3, nitrogen, N—Rb3, oxygen, or sulfur, and
A 4 represents carbon or nitrogen;
wherein at least one of A 1 , A 2 , A 3 , and A 4 is at least one member selected from the group consisting of nitrogen, N—Rb1, N—Rb2, N—Rb3, oxygen, and sulfur,
Rb1 represents hydrogen, halogen, C1-C6 alkyl that may have substituent R 71 , C3-C7 cycloalkyl that may have substituent R 74 , C4-C7 cycloalkenyl, a monocyclic 4- to 7-membered saturated heterocyclic group having one nitrogen or oxygen that may have substituent R 77 , or a monocyclic 5- to 8-membered unsaturated heterocyclic group having one nitrogen,
R 71 represents halogen, C1-C6 alkoxy, C3-C7 cycloalkyl, C6-C10 aromatic hydrocarbon that may have C1-C6 alkoxy as a substituent, a monocyclic 4- to 7-membered saturated heterocyclic group having one nitrogen that may have C1-C6 alkyl as a substituent, a monocyclic 5- to 8-membered unsaturated heterocyclic group having one nitrogen, or di(C1-C6 alkyl)amino,
R 74 represents hydroxyl or C1-C6 alkoxy,
R 77 represents C1-C6 alkyl that may have halogen or C6-C10 aromatic hydrocarbon as a substituent, C2-C6 alkenyl, (C1-C6 alkyl) carbonyl, (C1-C6 alkoxy) carbonyl, a monocyclic 4- to 7-membered saturated heterocyclic group having one nitrogen or oxygen, or a monocyclic 5- to 8-membered unsaturated heterocyclic group having one nitrogen,
Rb2 represents hydrogen or C1-C6 alkyl, and
Rb3 represents hydrogen, halogen, or C1-C6 alkyl that may have halogen as a substituent.
9 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I), R 5 is vinyl or dimethylamino-1-propenyl.
10 . The phenol compound or a salt thereof according to claim 1 , wherein in the Formula (I),
ring A represents
wherein
represents a single bond or a double bond,
A 1 represents C—Rb1, nitrogen, N—Rb1, oxygen, or sulfur,
A 2 represents C—Rb2, nitrogen, N—Rb2, oxygen, or sulfur,
A 3 represents C—Rb3, nitrogen, N—Rb3, oxygen, or sulfur, and
A 4 represents carbon or nitrogen;
wherein at least one of A 1 , A 2 , A 3 , and A 4 is at least one member selected from the group consisting of nitrogen, N—Rb1, N—Rb2, N—Rb3, oxygen, and sulfur,
Rb1 represents hydrogen, C1-C6 alkyl that may have substituent R 71 , or C3-C7 cycloalkyl,
R 71 represents C1-C6 alkoxy, C6-C10 aromatic hydrocarbon, a monocyclic 5- to 8-membered unsaturated heterocyclic group having one nitrogen, or di(C1-C6 alkyl)amino,
Rb2 represents hydrogen or C1-C6 alkyl, and
Rb3 represents hydrogen, halogen, or C1-C6 alkyl that may have halogen as a substituent.
11 . A compound according to any one of the following (1) to (23), or a salt of the compound according to any one of the following (1) to (23):
(1) N-(1-acryloylazetidin-3-yl)-5-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-N-methylfuran-2-carboxamide,
(2) N-(1-acryloylazetidin-3-yl)-5-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-N-ethylfuran-2-carboxamide,
(3) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1-methyl-1H-imidazole-5-carboxamide,
(4) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-4-methylthiazole-5-carboxamide,
(5) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-4-iodo-1-methyl-1H-imidazole-5-carboxamide,
(6) N-(1-acryloylazetidin-3-yl)-4-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-N-methylthiazole-2-carboxamide,
(7) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1-ethyl-1H-imidazole-5-carboxamide,
(8) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1-(2-methoxyethyl)-1H-imidazole-5-carboxamide,
(9) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1-(2-(dimethylamino)ethyl)-1H-imidazole-5-carboxamide,
(10) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide,
(11) N-(1-acryloylazetidin-3-yl)-1-benzyl-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-4-methyl-1H-imidazole-5-carboxamide,
(12) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1-ethyl-4-methyl-1H-imidazole-5-carboxamide,
(13) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1-isopropyl-4-methyl-1H-imidazole-5-carboxamide,
(14) N-(1-acryloylazetidin-3-yl)-1-butyl-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-4-methyl-1H-imidazole-5-carboxamide,
(15) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-4-methyl-1-propyl-1H-imidazole-5-carboxamide,
(16) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-1-cyclopentyl-4-methyl-1H-imidazole-5-carboxamide,
(17) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino) methyl)-4-methyl-1-(pyridin-3-ylmethyl)-1H-imidazole-5-carboxamide,
(18) N-(1-acryloylazetidin-3-yl)-2-(((5-(tert-butyl)-2-hydroxy-4-methylphenyl)amino)methyl)-1,4-dimethyl-1H-imidazole-5-carboxamide,
(19) N-(1-acryloylazetidin-3-yl)-2-(((6-(tert-butyl)-5-chloro-3-hydroxypyridin-2-yl)amino)methyl)-1-methyl-1H-imidazole-5-carboxamide,
(20) (E)-2-(((5-(tert-butyl)-4-chloro-2-hydroxyphenyl)amino)methyl)-N-(1-(4-(dimethylamino) but-2-enoyl) azetidin-3-yl)-1-methyl-1H-imidazole-5-carboxamide,
(21) N-(1-acryloylazetidin-3-yl)-2-(5-(tert-butyl)-4-chloro-2-hydroxybenzyl)-1,4-dimethyl-1H-imidazole-5-carboxamide,
(22) N-(1-acryloylazetidin-3-yl)-1-(5-(tert-butyl)-4-chloro-2-hydroxybenzyl)-3,5-dimethyl-1H-pyrazole-4-carboxamide, and
(23) N-(1-acryloylazetidin-3-yl)-2-(5-(tert-butyl)-4-chloro-2-hydroxybenzyl)-1-methyl-1H-imidazole-5-carboxamide.
12 . A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 , and a pharmaceutically acceptable carrier.
13 . An antitumor agent comprising the compound or a salt thereof according to claim 1 as an active ingredient.
14 . An antitumor agent comprising the compound or a salt thereof according to claim 1 , and one or more other antitumor agents, as active ingredients.
15 . A method of treating a tumor comprising administering an antitumor agent to a subject in need thereof in combination with one or more other antitumor agents, the antitumor agent comprising the compound or a salt thereof according to claim 1 as an active ingredient.
16 . A KRAS G12C mutant inhibitor comprising the compound or a salt thereof according to claim 11 as an active ingredient.
17 . A pharmaceutical composition comprising the compound or a salt thereof according to claim 11 , and a pharmaceutically acceptable carrier.
18 . An antitumor agent comprising the compound or a salt thereof according to claim 11 as an active ingredient.
19 . An antitumor agent comprising the compound or a salt thereof according to claim 11 , and one or more other antitumor agents, as active ingredients.
20 . A method of treating a tumor comprising administering an antitumor agent to a subject in need thereof in combination with one or more other antitumor agents, the antitumor agent comprising the compound or a salt thereof according to claim 11 as an active ingredient.