Granted Patent B2

US 12,378,255 · App. 18/484,588 · Granted Aug 5, 2025

Inventors: Albert Frederick Candia, III (San Mateo, CA); Richard Thomas Beresis (San Francisco, CA); Robert L. Coffman (Portola Valley, CA)

Assignee: DYNAVAX TECHNOLOGIES CORPORATION

C07D487/04A61K45/06C07D231/56C07D235/18C07D519/00

Abstract

Claims (103)

1. A method of inhibiting the production of a cytokine in a subject in need thereof, comprising:

administering to the subject a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

wherein:

A 1 is C or N;

A 2 is CR 2 , N, or NR 2a ;

A 3 is CR 30 , N, or NR 3a ;

A 4 is N or CR 4 ;

A 5 is N or CR 5 ;

provided that two, three, or four of A 1 , A 2 , A 3 , A 4 , and A 5 are N; wherein the dashed lines indicate partial or delocalized bonds in an aromatic ring;

i and j are independently 0, 1, or 2;

R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 2 , R 3 , R 30 , R 4 , and R 5 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 2a and R 3a is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 6 , where present, is independently C 1 -C 6 alkyl optionally substituted by R 10A ;

n is 0, 1, 2, 3, or 4;

U is a bond or methylene optionally substituted by R 10 ;

V is a bond or C 1 -C 2 alkylene optionally substituted by R 10 ;

W is a bond or C 1 -C 4 alkylene optionally substituted by one or both of R W1 and R W2 ;

X is —CR X1 R X2 —;

Y is —CR Y1 R Y2 —;

R 7 is hydrogen, C 1 -C 6 alkyl, or taken together with R 8 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R X1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 ;

R 8 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 , C 6 -C 14 aryl, 5-10-membered heteroaryl, or taken together with R 7 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R X1 , R X2 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R 10 , where present, to form a C 1 -C 6 alkylene, or taken together with R 9 and the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R 9 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 , or taken together with R 8 and the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R W1 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 , or R Y1 to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R W2 , R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R W2 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R W1 , R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R X1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R Y1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R X2 is hydrogen or C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R X1 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R 8 to form a C 1 -C 6 alkylene optionally substituted by R 10 ;

R Y1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R Y2 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R 8 to form a C 1 -C 6 alkylene optionally substituted by R 10 ;

each R 10 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -C 14 aryl, halogen, —CN, —OR 11 , —SR 11 , —NR 12 R 13 , —NO 2 , —C═NH(OR 11 ), —C(O) R 11 , —OC(O) R 11 , —C(O)OR 11 , —C(O) NR 12 R 13 , —NR 11 C(O) R 12 , —NR 11 C(O) OR 12 , —NR 11 C(O) NR 12 R 13 , —S(O) R 11 , —S(O) 2 R 11 , —NR 11 S(O) R 12 , —NR 11 S(O) 2 R 12 , —S(O) NR 12 R 13 , —S(O) 2 NR 12 R 13 , or —P(O) (OR 12 ) (OR 13 ); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl and C 6 -C 14 aryl of R 10 are independently optionally substituted by halogen, —CN, oxo, —OR 14 , —SR 14 , —NR 14 R 15 , —C(O) R 14 , —C(O) OR 14 , —S(O) R 14 , —S(O) 2 R 14 , —P(O) (OR 14 ) (OR 15 ), 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -C 14 aryl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen, or taken together with R 8 to form a C 1 -C 6 alkylene;

each R 10A is independently oxo or R 10 ;

R 11 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, or 3-6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, and 3-6-membered heterocyclyl of R 11 are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17 , —P(O) (OR 16 ) (OR 17 ), or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

R 12 and R 13 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, or 3-6 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, and 3-6 membered heterocyclyl of R 12 and R 13 are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17 or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

or R 12 and R 13 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 16 , —NR 16 R 17 , or C 1 -C 6 alkyl optionally substituted by halogen, oxo, or—OH;

R 14 and R 15 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;

or R 14 and R 15 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, or C 1 -C 6 alkyl optionally substituted by halogen or oxo; and

R 16 and R 17 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;

or R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, or C 1 -C 6 alkyl optionally substituted by oxo or halogen;

provided that when R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , and the 5-10-membered heteroaryl is a fused ring heteroaryl comprising an aryl moiety fused to a heterocycle containing the nitrogen atom to which R 8 and R 9 are attached, the aryl moiety is not adjacent to the nitrogen atom to which R 8 and R 9 are attached.

2. The method of claim 1 , wherein at least one applies:

(a) A 1 is N, A 2 is CR 2 and A 3 is N;

(b) A 1 is C, A 2 is CR 2 or NR 2a and A 3 is NH;

(c) A 4 is N and A 5 is N;

(d) A 4 is N and A 5 is CR 5 ;

(e) A 4 is CR 4 and A 5 is CR 5 .

3. The method of claim 1 , wherein at least one applies:

(a) R 2a is C 1 -C 6 alkyl;

(b) R 4 is hydrogen;

(c) R 5 is hydrogen.

4. The method of claim 1 , wherein the compound is at least one of the following:

(a) the compound of formula (Ia):

(b) the compound of formula (II):

(c) the compound of formula (IIa):

(d) the compound of formula (III):

and

(e) the compound of formula (IIIa):

5. The method of claim 1 , wherein i is 2 and j is 1 or 2; or wherein i is 1 and j is 2; or wherein i is 1 and j is 1; or wherein i is 1 and j is 0; or wherein i is 0 and j is 0.

6. The method of claim 1 , wherein at least one applied:

(a) U is a bond;

(b) V is a bond;

(c) V is ethylene (—CH 2 CH 2 —).

7. The method of claim 1 , wherein: n is 0; or n is 1 or 2 and each R 6 is independently C 1 -C 6 alkyl optionally substituted by R 10A .

8. The method of claim 1 , wherein R 1 is phenyl optionally substituted by R 10A .

9. The method of claim 1 , wherein at least one applies:

(a) R 2 is C 1 -C 6 alkyl;

(b) R 3 is C 1 -C 6 alkyl;

(c) R 7 is hydrogen or C 1 -C 6 alkyl;

(d) W is a bond;

(e) W is C 1 -C 4 alkylene optionally substituted by one or both of R W1 and R W2 ;

(f) each of R X1 and R X2 is independently hydrogen or C 1 -C 6 alkyl;

(g) each of R Y1 and R Y2 is independently hydrogen or C 1 -C 6 alkyl;

(h) R 8 is hydrogen or C 1 -C 6 alkyl;

(i) R 9 is hydrogen or C 1 -C 6 alkyl optionally substituted by R 10 ;

(j) R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 ;

(k) R Y1 , R Y2 , R 8 and R 9 are taken together with the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

(l) R X1 and R 8 are taken together to form a methylene (—CH 2 —);

(m) R Y1 and R 8 are taken together to form a propylene (—CH 2 CH 2 CH 2 —);

(n) R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 are taken together with the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

(o) R 7 and R 8 are taken together to form an ethylene optionally substituted by R 10 .

10. The method of claim 1 , wherein the —N(R 7 )—W—X—Y—N(R 8 ) R 9 moiety is selected from the group consisting of:

11. The method of claim 1 , wherein the compound is at least one of:

(a) the compound of formula (IIa-1a-2):

(b) the compound of formula (IIa-1b-2):

(c) the compound of formula (IIa-1c-1):

(d) the compound of formula (IIa-1d-2):

(e) the compound of formula (IIa-1e-2):

(f) the compound of formula (IIa-1f-2):

(g) the compound of formula (VIII-a-2):

12. The method of claim 11 , or a salt or solvate thereof, wherein at least one applies:

(a) V is a bond;

(b) V is C 1 -C 2 alkylene;

(c) R 2 and R 3 are independently hydrogen or C 1 -C 6 alkyl;

(d) k is 1 or 2;

(e) n is 1 and R 6 is C 1 -C 6 alkyl;

(f) n is 0;

(g) R 8 and R 9 are independently C 1 -C 6 alkyl optionally substituted by R 10 ;

(h) R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl;

(i) R 10 is C 6 -C 14 aryl.

13. The method of claim 1 , wherein the cytokine is tumor necrosis factor-alpha.

14. The method of claim 1 , wherein the cytokine is interleukin-1 beta.

15. The method of claim 1 , wherein the cytokine is interleukin-6.

16. The method of claim 1 , wherein the cytokine is interferon-alpha.

17. The method of claim 1 , wherein the cytokine is selected from the group consisting of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, and interferon-alpha.

Assignments (1)

Continuity (5)

References Cited (28)