JP2016529264A5

JP2016529264A5 -

Info

Publication number: JP2016529264A5
Application number: JP2016537144A
Authority: JP
Filing date: 2013-09-03
Publication date: 2016-11-04
Anticipated expiration: 2033-09-03

Claims

A compound that is an amide of 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
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 ring selected from pyrrolidine and piperidine (the heterocyclic ring may be substituted with a methyl group)
Selected from;
R ² , if 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, and the heterocyclic ring may be substituted with a hydroxymethyl group ;
(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, one of R ^{3 to} R ⁵ is chlorine or Is fluorine and / or R ¹ -AQ ¹ is selected from ethylsulfonyl and isopropylsulfonyl].

The compound of claim 1, wherein when R ⁷ and R ⁶ are both fluorine, one of R ^{3 to} R ⁵ is chlorine or fluorine.

The compound of claim 1, wherein R ⁷ is chlorine.

R ⁶ R ⁷ is chlorine is fluorine compound according to claim 3.

R ⁷ and R ⁶ are both chlorine, a compound of claim 3.

At least one of R ³ and R ⁵ are hydrogen, A compound according to any one of claims 1 to 5.

R ^３3 , R ^４4 And R ^５5 7. A compound according to claim 6, wherein is hydrogen.

Q ^１1 The compound according to any one of claims 1 to 7, wherein is C (= O).

A is NR ^２2 And NR ^１1 R ^２2 Forms a 5- to 6-membered heterocyclic ring selected from pyrrolidine and morpholine, wherein the heterocyclic ring may be substituted with a hydroxymethyl group.

A does not exist, Q ^１1 Is SO _２2 And R ^１1 Is C _１〜３1-3 The compound according to any one of claims 1 to 7, which is an alkyl group.

Q ^{¹ -A-R} ¹ is a group AA in the table below, AG, AH, AI, AR , selected from the AS and AT, the compounds according to any one of claims 1 to 7:

[Wherein the point of attachment to the phenyl group is indicated by an asterisk].

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 ; and 2- (2,6-difluoro-phenyl) -5- [4- Propan-2-sulfonyl) -henylamino] -oxazole-4-carboxylic acid amide;
Compounds and salts and stereoisomers thereof of claim 1 which is selected from.

A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 12 and a pharmaceutically acceptable additive.

13. A compound according to any one of claims 1 to 12 for use in medicine.

(A) Treatment of a disease or condition in a subject in need thereof, wherein the disease is selected from inflammatory diseases or conditions, immune diseases or conditions, allergic diseases or disorders, transplant rejection and graft-versus-host disease , said disease or condition is sensitive to inhibition TYK2, an effective TYK2 inhibitory amount of the compound treatment comprising administering to said subject; in the treatment of autoimmune diseases in a subject in need thereof or (B) A treatment comprising administering to said subject an effective TYK2 inhibitory amount of said compound to inhibit TYK2 kinase in said subject, thereby blocking or reducing the magnitude of the inflammatory process associated with autoimmune disease; or (C) it to the treatment of a disease or condition in a subject in need thereof, said disease is other than autoimmune diseases Selected from symptomatic disease or condition, immune disease or condition, allergic disease or disorder, transplant rejection and graft-versus-host disease, wherein the disease or condition is sensitive to TYK2 inhibition, and an effective TYK2 inhibitory amount of said compound It said treatment comprising administering to the subject; or (D) a that treatment of a disease or condition in a subject in need thereof, skin inflammation due to the disease is (a) exposure to radiation;
(B) asthma;
(C) allergic inflammation;
(D) chronic inflammation;
(E) inflammatory eye diseases;
(F) Dry eye syndrome (also known as DES, dry keratoconjunctivitis or tear dysfunction syndrome);
(G) uveitis (eg, a chronic progressive or recurrent form of unaffected uveitis);
(H) insulin dependent diabetes mellitus (type I);
(I) Hashimoto's thyroiditis;
(J) Graves'disease;
(K) Cushing's disease;
(L) Addison disease (afflicted with adrenal glands)
(M) chronic active hepatitis (affected liver);
(N) polycystic ovary syndrome (PCOS);
(O) Pediatric steatosis;
(P) psoriasis;
(Q) inflammatory bowel disease (IBD);
(R) ankylosing spondylitis;
(S) rheumatoid arthritis;
(T) systemic lupus erythematosus;
(U) myasthenia gravis;
(V) transplant rejection (allograft rejection); and (w) graft-versus-host disease (GVDH);
Any one or more diseases or conditions selected from, wherein the disease may be further selected from (x) sepsis and septic shock; and (y) multiple sclerosis, Treatment comprising administering to said subject a TYK2 inhibitory amount; or (E) diagnosis and treatment of a disease state or condition mediated by TYK2 kinase, comprising: (i) screening a patient to afflict said patient; Determining whether the disease or condition that is or can be affected is a disease or condition that would be susceptible to treatment with a compound having activity against said kinase; (ii) the patient may be affected Diagnosis and treatment comprising, if a disease or condition is indicated, then administering an effective TYK2 inhibitory amount of said compound to said patient
A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 for use.