JPWO2020123925A5

JPWO2020123925A5 -

Info

Publication number: JPWO2020123925A5
Application number: JP2021533779A
Authority: JP
Publication date: 2022-12-21

Claims

Formula (I):

In the formula:
R ¹ is optionally substituted aryl or optionally substituted heteroaryl;
^R2 , R3 ^, ^R4 , and ^R5 are each independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl , optionally substituted heteroaryl, -NO2, -CN, -SCN, -OR ^D1 , -N ₍ R ^D1 ) ₂ , or -SR ^D1 , where R ^D1 is independently hydrogen, optionally substituted acyl , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, when attached to an oxygen atom an oxygen protecting group, when attached to a nitrogen atom a nitrogen protecting group, or a sulfur protecting group when attached to a sulfur atom;
n is 1, 2, or 3;
m is 1, 2, 3, or 4;
L ¹ is O, S, or -N(R ^a )-, where R ^a is hydrogen, optionally substituted acyl, optionally substituted C _1-6 alkyl, or a nitrogen protecting group;
L2 is O, S, -N ⁽ R ^L2a )-, -C=O-, -N(R ^L2a )C(=O)-, or -C(=O)N(R ^L2a )- , where R ^L2a is hydrogen, optionally substituted acyl, optionally substituted C _1-6 alkyl, or a nitrogen protecting group;
V ¹ is C(R ^1a )H;
V2 is ^C ( ^R1b )H;
^{V3 is N or C(R1c} ⁾ ;
R ^1a and R ^1b are independently hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN , -OR ^C1 , -N(R ^C1 ) ₂ , or -SR ^C1 , where R ^C1 is independently hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom is a group, or R ^1a and R ^1b are joined together to form an optionally substituted bridged ring;
R ^1c is hydrogen or substituted or unsubstituted C _1-6 alkyl;
p is 1, 2, or 3;
D ¹ is represented by formulas (i-1) to (i-42):

is a warhead represented by any one of ; where:
L ³ is a bond or an optionally substituted C _1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently -O-, -S-, -NR ^L3a -, -NR ^L3a C(=O)-, -C(=O)NR ^L3a -, -SC(=O)-, -C(=O)S-, -OC(=O)-, -C(=O )O-, -NR ^L3a C(=S)-, -C(=S)NR ^L3a -, trans-CR ^L3b =CR ^L3b -, cis-CR ^L3b =CR ^L3b -, -C≡C-, -S (=O)-, -S(=O)O-, -OS(=O)-, -S(=O)NR ^L3a -, -NR ^L3a S(=O)-, -S(=O) ₂ -, -S(=O) ₂ O-, -OS(=O) ₂ -, -S(=O) ₂ NR ^L3a -, or -NR ^L3a S(=O) ₂ -, here wherein R ^L3a is hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of R ^L3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R ^L3b groups joined together to optionally substituted carbocyclic or form an optionally substituted heterocyclic ring;
L ⁴ is a bond or an optionally substituted C _1-4 hydrocarbon chain;
R ^E1 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, _-CH2OR ^E1a , _-CH2N (R ^E1a ) ₂ , -CH ₂ SR ^E1a , -OR ^E1a , -N(R ^E1a ) ₂ , -Si(R ^E1a ) ₃ , and -SR ^E1a , wherein each occurrence of R ^E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or two are joined to form an ^optionally substituted heterocyclic ring;
R ^E2 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, ^{-CH2OR E2a} _, _-CH2N (R ^E2a ) ₂ , -CH ₂ SR ^E2a , -OR ^E2a , -N(R ^E2a ) ₂ , and -SR ^E2a , wherein each occurrence of R ^E2a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or two R ^E2a groups are linked to form an optionally substituted heterocyclic ring;
R ^E3 is hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, -CN, ^{-CH2OR E3a} _, _-CH2N (R ^E3a ) ₂ , -CH ₂ SR ^E3a , -OR ^E3a , -N(R ^E3a ) ₂ , and -SR ^E3a , wherein each occurrence of R ^E3a is independently hydrogen, is selected from the group consisting of optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; or the two R ^E3a groups are , joined to form an optionally substituted heterocyclic ring;
Alternatively, R ^E1 and R ^E3 , or R ^E2 and R ^E3 , or R ^E1 and R ^E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
R ^E4 is a leaving group;
R ^E5 is halogen;
Y is O, S, or NR ^E6 , where R ^E6 is hydrogen, substituted or unsubstituted C _1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6;
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

2. The compound of claim ¹ , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein L1 is -N(Ra)-.

3. The compound of claim ¹ , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein L1 is -NH-.

4. The compound of claim 1, 2 or ³ , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein V3 is N.

Formula (II):

In the formula:
p is 1, 2, or 3;
5. The compound of claim 4 represented by or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

Formula (III):

5. The compound of claim 4 represented by or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

7. The compound of any one of claims 1 to 6 , or a pharmaceutically acceptable compound thereof, wherein L2 is -( ^C =O)- or -(C=O)N(R ^L2a )- Salts, solvates, hydrates, tautomers, or stereoisomers.

4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein ^{V3 is C(Rlc} ⁾ .

9. The compound of Claim 8 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein V1 is ^C ( ^Rla )(H) .

10. ^The compound of claim 8 or 9 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer thereof, wherein V2 is -C( ^R1b )(H)-; or stereoisomers.

11. The compound according to any one of claims 8 to 10 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer thereof, wherein L2 is -N ⁽ R ^L2a ) - body, or stereoisomer.

Formula (IV):

2. The compound of claim 1 , represented by or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

13. The compound of any one of claims 1-12 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereomer thereof, wherein R ¹ is optionally substituted aryl Isomer.

14. The compound of any one of claims 1-13 , wherein R ³ is H, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof .

15. The compound of any one of claims 1-14 , wherein ^R4 is H, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof .

D ¹ is the formula:

A compound according to any one of claims 1 to 15 , represented by

The compound has the formula:

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, represented by.

A compound according to any one of claims 1 to 17 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically A pharmaceutical composition comprising an acceptable excipient.

19. A pharmaceutical composition according to claim 18 for use in treating proliferative , inflammatory, autoimmune or cardiovascular diseases .

A method of inhibiting the activity of c-Jun N-terminal kinase (JNK) in a biological sample, the method comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17 , or The above method, comprising contacting a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof with a biological sample.