JPWO2019213445A5

JPWO2019213445A5 -

Info

Publication number: JPWO2019213445A5
Application number: JP2021510283A
Authority: JP
Publication date: 2022-04-13
Anticipated expiration: 2039-05-02

Claims

formula

(Ring B in the formula is a 5-membered heteroaryl;
L is a C _1-10 aliphatic linker;
R ¹ is R ^a or R ^b , and at least one R ¹ is R ^b ;
Each of R ² and R ³ is independently ^Ra ;
Each R ⁴ and each R ⁵ are independently R ^a or R ^b ;
R ^a is an H, D, C _1-10 aliphatic or C _1-10 cyclic aliphatic independently in each case;
R ^b are independently -NR ^d R ^d in each case, and (i) each R ^d is independently ^Ra or ^Re ; or (ii) two R ^d groups. Provides a _C3-10 heterocyclic group, together with the nitrogen to which they are attached;
^Re is independently in each case -OR ^a , -NR ^a , C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 heteroalkyl, C _3-6 cyclic alkyl, or The two ^{Re groups together provide a C3-10 heterocyclic group together with the R b} _group ^to which the two ^Re groups are attached;
m is 1 to 4;
n is 0, 1 or 2; and p is 0, 1, 2, 3, 4 or 5)
A compound having or a pharmaceutically acceptable salt thereof.

formula

The compound according to claim 1, which has a structure satisfying the above conditions.

Ring B is the formula

(In the formula, at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen or NH).
The compound according to claim 1 or 2, which has a structure satisfying the above conditions.

Ring B is

Triazole selected from, or

The compound according to any one of claims 1 to 3, which is an oxazole selected from the above.

R ⁵ is R ^a , R ^a is C ₁ to C ₄ aliphatic; and / or R ² is R ^a and R ^a is C ₁ to C ₄ aliphatic. The compound according to any one of claims 1 to 4, wherein R ³ is ^Ra and ^Ra is hydrogen.

R ¹ is R ^b , R ^b is -NR ^d R ^d , and the two R ^d groups together with the nitrogen to which they are attached form two ^Re groups. Any of claims 1-5, which provides a C _3-10 heterocyclic group comprising, wherein the two ^Re groups together provide a second C _3-10 heterocyclic group. The compound according to one item.

The second C _{3 to 10} heterocycle formed by the two ^{Re groups and the C 3 to 10 heterocycle formed by the two R d} _groups ^of R ^b may be a spirocyclic group or a spirocyclic group. The compound according to claim 6, which provides a bicyclic group.

The spirocyclic group comprises at least two rings, the first ring and the second ring of the spirocyclic group having different numbers of carbon atoms, different numbers of heteroatoms or both. The compound according to claim 6 or 7, wherein each ring of the spirocyclic group contains a heteroatom in the ring.

The compound according to any one of claims 6 to 8, wherein the spiro cyclic group contains at least one oxygen atom and at least one nitrogen atom.

The spirocyclic group is a first ring coupled to a carbon atom of the compound, a first ring having 3 to 7 atoms and a second ring having 3 to 7 atoms. The compound according to any one of claims 6 to 9, comprising the ring of.

The compound according to any one of claims 6 to 10, wherein the spiro cyclic group contains a total of more than 7 atoms in the spiro ring system.

The C _3-10 heterocycle formed by the two ^{Re groups and the C 3-10 heterocycle formed by the two R d} _groups ^of R ^b provide a bicyclic group. The compound according to any one of claims 6 to 11, wherein the bicyclic group contains two or more heteroatoms in the bicyclic group.

The bicyclic group is a fused bicyclic group or a crosslinked bicyclic group, and the bicyclic group is bonded to a phenyl group which is ring A of the formula I through a nitrogen atom of the bicyclic group. The compound according to claim 12.

R ¹ is

(In the equation, each n is independently an integer in the range ^0-4 , and R6 is independently selected from hydrogen, aliphatic, aromatic or complex aliphatic).
The compound according to any one of claims 1 to 13.

The compound according to any one of claims 1 to 14, which is selected from the above.

The compound according to any one of claims 1 to 15.

A pharmaceutical composition comprising the compound, additive, therapeutic agent, adjuvant or a combination thereof according to any one of claims 1 to 15.

A drug comprising the compound according to any one of claims 1 to 15 or the pharmaceutical composition according to claim 17, wherein the receptor-interacting protein-1 (RIP1) kinase is used as the compound or the pharmaceutical composition. A drug characterized by including contact with an object.

(I) The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, a stereoisomer, an N-oxide, a tautomer, a hydrate, a solvent, an isotope thereof. Alternatively, a prodrug; or (ii) a drug for treating a subject disease, comprising the pharmaceutical composition according to claim 16, wherein a therapeutically effective amount of the compound or a pharmaceutically acceptable thereof is acceptable to the subject. It comprises administering a salt, a steric isomer, an N-oxide, a tautomer, a hydrate, a solvate, an isotope or a prodrug; or a therapeutically effective amount of the pharmaceutical composition. A drug , wherein the subject has, or is suspected of having, or develops the disease, the disease being a disease involving a receptor-interacting protein-1 (RIP1) kinase.

A method for producing the compound according to any one of claims 1 to 15.
The starting material having the formula A is a reagent containing R ¹ , the reagent containing R ¹ having the formula R ¹ −H, and the reagent containing the starting material and the reagent R ¹ are transition metal catalysts. Coupling by combining with a ligand component and a solvent to produce a product functionalized with ^R1 ;
To provide an amine compound by deprotecting the amine group of the product functionalized with ^R1 ;
It comprises forming an amide bond between the amine compound and a coupling partner containing an acid.
Equation A is

And;
The product functionalized with R ¹ is of formula B.

It has a structure that satisfies; and the coupling partner containing the acid is of formula C.

Has a structure that satisfies;
X is a halogen or triflate;
PG is an amine protecting group; and rings B, L, R ¹ , R ² , R ⁴ , R ⁵ , m, n and p, respectively, are as described in claim 1.

The method of claim 20, wherein the amide bond is formed by coupling the amine compound to a coupling partner containing the acid in the presence of propylphosphonic anhydride and diisopropylethylamine.