US2013231340A1PendingUtilityA1
Pharmaceutical compounds
Est. expiryMar 2, 2032(~5.6 yrs left)· nominal 20-yr term from priority
Inventors:John Charles Reader
A61P 37/06A61P 29/00A61P 17/06C07D 263/48C07D 413/12
54
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Claims
Abstract
The invention provides a method of inhibiting a TYK2 kinase, which method comprises bringing into contact with the TYK2 kinase an effective TYK2 kinase-inhibiting amount of a compound having the formula (0): or a salt or stereoisomer thereof. The invention also provides a novel subset of compounds within formula (0) as well as pharmaceutical compositions containing them and their use in medicine.
Claims
exact text as granted — not AI-modified1 . A method of inhibiting a TYK2 kinase, which method comprises bringing into contact with the TYK2 kinase an effective TYK2 kinase-inhibiting amount of a compound having the formula (0):
or a salt or stereoisomer thereof; wherein:
n is 0, 1 or 2;
Ar 1 is selected from phenyl, pyridyl, thienyl and furanyl, each of which is optionally substituted with one, two or three substituents independently selected from halogen, C 1-4 alkyl, hydroxyl-C 1-4 alkyl, C 1-2 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, C 1-2 alkoxy-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, C 2-4 alkynyl, C 2-4 alkynyloxy, cyano, C 1-4 alkanoyl, hydroxy and C 1-4 alkanoyloxy, wherein the C 1-4 alkyl and C 1-4 alkoxy moieties are each optionally substituted with one or more fluorine atoms;
Q 1 is selected from C(═O), S(═O) and SO 2 ;
A is absent or is NR 2 ;
R 1 is selected from:
hydrogen;
a C 1-6 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from hydroxyl, C 1-2 alkoxy, amino, mono-C 1-4 alkylamino, alkylamino, 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms, the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyl or hydroxyl-C 1-3 alkyl groups; and
3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms, the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyl, amino-C 1-3 alkyl, mono-C 1-2 alkylamino-C 1-3 alkyl, di-C 1-2 alkylamino-C 1-3 alkyl or hydroxyl-C 1-3 alkyl groups;
R 2 is selected from hydrogen and C 1-4 alkyl; or
NR 1 R 2 forms a 4- to 7-membered non-aromatic nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxy, C 1-4 alkoxycarbonyl mono-C 1-2 alkylamino-C 1-3 alkyl, di-C 1-2 alkylamino-C 1-3 alkyl or hydroxy-C 1-3 alkyl groups.
2 . A method according to claim 1 wherein the method comprises bringing into contact with the TYK2 kinase an effective TYK2 kinase-inhibiting amount of a compound having the formula (1):
or a salt or stereoisomer thereof; wherein:
Ar 1 is selected from phenyl, pyridyl, thienyl and furanyl, each of which is optionally substituted with one, two or three substituents independently selected from halogen, C 1-4 alkyl, hydroxyl-C 1-4 alkyl, C 1-2 alkoxy-C 1-4 alkyl, C 1-4 alkoxy, C 1-2 alkoxy-C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkenyloxy, C 2-4 alkynyl, C 2-4 alkynyloxy, cyano, C 1-4 alkanoyl, hydroxy and C 1-4 alkanoyloxy, wherein the C 1-4 alkyl and C 1-4 alkoxy moieties are each optionally substituted with one or more fluorine atoms;
Q 1 is selected from C(═O), S(═O) and SO 2 ;
A is absent or is NR 2 ;
R 1 is selected from:
hydrogen;
a C 1-6 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from hydroxyl, C 1-2 alkoxy, amino, mono-C 1-4 alkylamino, alkylamino, 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms, the carbocylic and heterocyclic rings and bridged bicyclic heterocyclic rings being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyl or hydroxyl-C 1-3 alkyl groups; and
3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms, the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyl, amino-mono-C 1-2 alkylamino-C 1-3 alkyl or hydroxyl-C 1-3 alkyl groups;
R 2 is selected from hydrogen and C 1-4 alkyl; or
NR 1 R 2 forms a 4- to 7-membered non-aromatic nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxy, C 1-4 alkoxycarbonyl mono-C 1-2 alkylamino-C 1-3 alkyl, alkylamino-C 1-3 alkyl or hydroxy-C 1-3 alkyl groups.
3 . A method according to claim 2 wherein the optional substituents for Ar 1 are independently selected from fluorine, chlorine, bromine, methyl, ethyl, isopropyl, hydroxymethyl, hydroxyethyl, methoxyethyl, methoxy, ethoxy, isopropoxy, methoxyethoxy, cyano, acetyl, acetoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl and difluoromethoxy.
4 . A method according to claim 3 wherein Ar 1 is selected from 2,6-difluorophenyl, 2-chloro-6-fluorophenyl and 2,6-dichlorophenyl.
5 . A method according to claim 2 wherein A is NR 2 and Q 1 is C(═O).
6 . A method according to claim 2 wherein A is absent and Q 1 is SO 2 .
7 . A method according to claim 2 wherein R 1 is selected from:
hydrogen;
a C 1-4 alkyl group optionally substituted with one or more substituents selected from hydroxy, amino and mono-C 1-3 alkylamino; and
5 to 6-membered heterocyclic rings selected from pyrrolidine, piperidine, piperazine and morpholine, the heterocyclic rings being optionally substituted with one or more C 1-3 alkyl or hydroxy-C 1-3 alkyl groups;
R 2 , when present, is selected from hydrogen and C 1-2 alkyl; or
NR 1 R 2 forms a 5 to 6-membered heterocyclic ring selected from pyrrolidine, piperidine, piperazine and morpholine, the heterocyclic ring being optionally substituted with one or more C 1-3 alkyl or hydroxy-C 1-3 alkyl groups.
8 . A method according to claim 7 wherein Q 1 -A-R 1 is selected from groups AA to AR in the table below:
AA
AB
AC
AD
AE
AF
AG
AH
AI
AJ
AK
AL
AM
AN
AO
AP
AQ
AR
wherein the point of attachment to the phenyl group is indicated by the asterisk.
9 . A method according to claim 2 wherein the compound of formula (1) is selected from:
2-(2,6-difluorophenyl)-5-(4-(methylsulfonyl)phenylamino)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(4-sulfamoylphenylamino)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(4-(N,N-dimethylsulfamoyl)phenylamino)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(4-(N′-methylsulfamoyl)phenylamino)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(4-(dimethylcarbamoyl)phenylamino)oxazole-4-carboxamide;
5-(4-((3-aminopropyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide;
(R)-2-(2,6-difluorophenyl)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole-4-carboxamide;
(S)-2-(2,6-difluorophenyl)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4-carboxamide;
5-(4-((2-(methylamino)ethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide;
5-(4-((3-(methylamino)propyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide;
(R)-2-(2,6-difluorophenyl)-5-(4-(pyrrolidin-3-ylcarbamoyl)phenylamino)oxazole-4-carboxamide;
(S)-2-(2,6-difluorophenyl)-5-(4-(pyrrolidin-3-ylcarbamoyl)phenylamino)oxazole-4-carboxamide;
(R)-2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)phenylamino)oxazole-4-carboxamide;
5-(4-((2-hydroxyethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide;
5-(4-((3-hydroxypropyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(4-(piperidin-4-ylcarbamoyl)phenylamino)oxazole-4-carboxamide; and
5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide;
and salts thereof.
10 . A compound which is an amide of the formula (2):
or a salt or stereoisomer thereof; wherein:
R 7 is selected from chlorine and fluorine;
R 3 , R 4 , R 5 and R 6 are each independently selected from hydrogen, fluorine and chlorine;
n is 0, 1 or 2;
Q 1 is selected from C(═O), S(═O) and SO 2 ;
A is absent or is NR 2 ;
R 1 is selected from:
hydrogen;
a C 1-6 non-aromatic hydrocarbon group optionally substituted with one or more substituents selected from hydroxyl, C 1-2 alkoxy, amino, mono-C 1-4 alkylamino, alkylamino, 3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms, the carbocylic and heterocyclic rings and bridged bicyclic heterocyclic rings being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkoxy, alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyl or hydroxyl-C 1-3 alkyl groups; and
3- to 7-membered non-aromatic carbocyclic and heterocyclic rings containing one or two heteroatom ring members selected from O, N and S, and bridged bicyclic heterocyclic rings of seven to nine ring members of which one or two are nitrogen atoms, the carbocyclic and heterocyclic rings and bridged bicyclic heterocyclic rings being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxycarbonyl, amino-mono-C 1-2 alkylamino-C 1-3 alkyl or hydroxyl-C 1-3 alkyl groups;
R 2 is selected from hydrogen and C 1-4 alkyl; or
NR 1 R 2 forms a 4- to 7-membered non-aromatic nitrogen-containing heterocyclic ring optionally containing a second heteroatom ring member selected from nitrogen and oxygen, the heterocyclic ring being optionally substituted with one or more hydroxy, C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkanoyloxy, C 1-4 alkoxy, C 1-4 alkoxycarbonyl mono-C 1-2 alkylamino-C 1-3 alkyl, alkylamino-C 1-3 alkyl or hydroxy-C 1-3 alkyl groups;
with the provisos that:
(i) no more than two of R 3 to R 6 are other than hydrogen; and
(ii) when R 7 and R 6 are both fluorine, then one of R 3 to R 5 is chlorine or fluorine and/or R 1 -A-Q 1 is selected from ethylsulfonyl and isopropylsulfonyl.
11 . A compound according to claim 10 provided that when R 7 and R 6 are both fluorine, then one of R 3 to R 5 is chlorine or fluorine.
12 . A compound according to claim 10 wherein R 7 is chlorine.
13 . A compound according to claim 10 wherein R 7 is chlorine and R 6 is fluorine.
14 . A compound according to claim 10 wherein R 7 and R 6 are both chlorine.
15 . A compound according to claim 10 wherein at least one of R 3 and R 5 is hydrogen.
16 . A compound according to claim 10 wherein:
R 1 is selected from:
hydrogen;
a C 1-3 alkyl group optionally substituted with one or more substituents selected from hydroxy, amino and methylamino; and
5 to 6-membered heterocyclic rings selected from pyrrolidine and piperidine, the heterocyclic rings being optionally substituted with a methyl group;
R 2 , when present, is selected from hydrogen and methyl; or
NR 1 R 2 forms a 5 to 6-membered heterocyclic ring selected from pyrrolidine and morpholine, the heterocyclic ring being optionally substituted with a hydroxymethyl group.
17 . A compound according to claim 10 wherein Q 1 -A-R 1 is selected from groups AA, AG, AH, AI, AR, AS and AT in the table below:
AA
AG
AH
AI
AS
AT
wherein the point of attachment to the phenyl group is indicated by the asterisk.
18 . A compound according to claim 17 which is selected from:
2-(2,6-dichloro-phenyl)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-carboxylic acid amide;
2-(2-chloro-6-fluoro-phenyl)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-carboxylic acid amide;
5-(4-methanesulfonyl-phenylamino)-2-(2,4,6-trifluoro-phenyl)-oxazole-4-carboxylic acid amide;
2-(2,5-difluoro-phenyl)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-carboxylic acid amide;
(S) 2-(2-chloro-6-fluoro-phenyl)-5-[4-(piperidin-3-ylcarbamoyl)-phenylamino]-oxazole-4-carboxylic acid amide;
(R) 2-(2-chloro-6-fluoro-phenyl)-5-[4-(piperidin-3-ylcarbamoyl)-phenylamino]-oxazole-4-carboxylic acid amide;
2-(2-chloro-6-fluoro-phenyl)-5-[4-(morpholine-4-carbonyl)-phenylamino]-oxazole-4-carboxylic acid amide;
2-(2-chloro-6-fluoro-phenyl)-5-[4-(1-methyl-piperidin-4-ylcarbamoyl)-phenylamino]-oxazole-4-carboxylic acid amide;
(S) 2-(2,6-dichloro-phenyl)-5-[4-(piperidin-3-ylcarbamoyl)-phenylamino]-oxazole-4-carboxylic acid amide;
(R) 2-(2,6-dichloro-phenyl)-5-[4-(piperidin-3-ylcarbamoyl)-phenylamino]-oxazole-4-carboxylic acid amide;
2-(2,6-dichloro-phenyl)-5-[4-(morpholine-4-carbonyl)-phenylamino]-oxazole-4-carboxylic acid amide;
2-(2,6-dichloro-phenyl)-5-[4-(1-methyl-piperidin-4-ylcarbamoyl)-phenylamino]-oxazole-4-carboxylic acid amide;
2-(2,6-difluoro-phenyl)-5-(4-ethanesulfonyl-phenylamino)-oxazole-4-carboxylic acid amide;
2-(2,6-difluoro-phenyl)-5-(4-methanesulfonyl-phenylamino)-oxazole-4-carboxylic acid amide; and
2-(2,6-difluoro-phenyl)-5-[4-propane-2-sulfonyl)-phenylamino]-oxazole-4-carboxylic acid amide;
and salts and stereoisomers thereof.
19 . A pharmaceutical composition comprising a compound as defined in claim 10 and a pharmaceutically acceptable excipient.
20 . A method of inhibiting a TYK2 kinase, which method comprises bringing into contact with the TYK2 kinase an effective TYK2 kinase-inhibiting amount of the compound of claim 10 .
21 . A method of therapy comprising:
(A) a method of treating a disease or condition in a subject in need thereof, wherein the disease is selected from an inflammatory disease or condition, an immunological disease or condition, an allergic disease or disorder, a transplant rejection and Graft-versus host disease wherein the disease or condition is susceptible to TYK2 inhibition, which method comprises administering to the subject an effective TYK2 inhibiting amount of the compound of claim 10 ; or (B) a method of treating an autoimmune disease in a subject in need thereof, which method comprises administering to the subject an effective TYK2 inhibiting amount of the compound of claim 10 so as to inhibit TYK2 kinase in the subject and thereby block or reduce the extent of an inflammatory process associated with the autoimmune disease; or (C) a method of treating a disease or condition in a subject in need thereof, wherein the disease is other than an autoimmune disease and is selected from an inflammatory disease or condition, an immunological disease or condition, an allergic disease or disorder, a transplant rejection and Graft-versus host disease wherein the disease or condition is susceptible to TYK2 inhibition, which method comprises administering to the subject an effective TYK2 inhibiting amount of a compound as defined in claim 10 ; or (D) a method of treating a disease or condition in a subject in need thereof, wherein the disease is any one or more diseases or conditions selected from:
(a) skin inflammation due to radiation exposure;
(b) asthma;
(c) allergic inflammation;
(d) chronic inflammation;
(e) an inflammatory ophthalmic disease;
(f) dry eye syndrome (DES, also known as keratoconjunctivitis sicca or dysfunctional tear syndrome);
(g) uveitis (e.g. chronic progressive or relapsing forms of non-infectious uveitis);
(h) insulin-dependent diabetes (Type I);
(i) Hashimoto's thyroiditis;
(j) Graves' disease;
(k) Cushing's disease;
(l) Addison's disease (which affect the adrenal glands)
(m) chronic active hepatitis (which affects the liver);
(n) polycystic ovary syndrome (PCOS);
(o) coeliac disease;
(p) psoriasis;
(q) inflammatory bowel disease (IBD);
(r) ankylosing spondylitis;
(s) rheumatoid arthritis;
(t) systemic lupus erythematosus;
(u) myasthenia gravis;
(v) transplant rejection (allograft transplant rejection); and
(w) graft-versus-host disease (GVDH);
wherein the disease is optionally further selected from:
(x) sepsis and septic shock; and
(y) multiple sclerosis;
which method comprises administering to the subject an effective TYK2 inhibiting amount of a compound as defined in claim 10 ; or (E) the diagnosis and treatment of a disease state or condition mediated by TYK2 kinase, which diagnosis and treatment comprises (i) screening a patient to determine whether a disease or condition from which the patient is or may be suffering is one which would be susceptible to treatment with a compound having activity against the kinase; and (ii) where it is indicated that the disease or condition from which the patient is thus susceptible, thereafter administering to the patient an effective TYK2 inhibiting amount of a compound as defined in claim 10 .Cited by (0)
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