Substituted imidazo[1,2-b]pyridazines and [1,2,4]triazolo[4,3-b]pyridazines as CaMKII inhibitors

1. A compound represented by formula (I):

or a pharmaceutically acceptable salt thereof,

wherein:

X 1 is CR X1 or N;

R X1 is H, halogen, or C 1-6 alkyl;

R X6 is H;

Y 1 is CR Y1 or N;

Y 2 is CR Y2 or N;

Y 3 is CR Y3 or N;

Y 4 is CR Y4 or N;

R Y1 is H;

R Y2 is H, halogen, or CN;

R Y3 is H or halogen;

R Y4 is H or halogen;

V is —O—;

Z is C 1-6 alkylene;

Ring A 1 is C 6-14 aryl or heteroaryl, wherein the C 6-14 aryl or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 7-16 aralkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)H, C(O)C 1-6 alkyl, C(O)C 1-6 haloalkyl, C(O)C 7-16 aralkyl, C(O)C 2-6 alkenyl, C(O)C 3-10 cycloalkyl, C(O)C 3-10 cycloalkenyl, C(O)-(3- to 14-membered heterocyclyl), C(O)C 6-14 aryl, C(O)-(5- to 14-membered heteroaryl), C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)NHC 1-6 haloalkyl, C(O)NHC 7-16 aralkyl, C(O)NHC 2-6 alkenyl, C(O)NHC 3-10 cycloalkyl, C(O)NHC 3-10 cycloalkenyl, C(O)NH-(3- to 14-membered heterocyclyl), C(O)NHC 6-14 aryl, C(O)NH-(5- to 14-membered heteroaryl), C(O)N(C 1-6 alkyl) 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 1-6 haloalkyl, C(O)OC 7-16 aralkyl, C(O)OC 2-6 alkenyl, C(O)OC 3-10 cycloalkyl, C(O)OC 3-10 cycloalkenyl, C(O)O-(3- to 14-membered heterocyclyl), C(O)OC 6-14 aryl, C(O)O-(5- to 14-membered heteroaryl), C(S)NH 2 , C(S)NHC 1-6 alkyl, C(S)NHC 1-6 haloalkyl, C(S)NHC 7-16 aralkyl, C(S)NHC 2-6 alkenyl, C(S)NHC 3-10 cycloalkyl, C(S)NHC 3-10 cycloalkenyl, C(S)NH-(3- to 14-membered heterocyclyl), C(S)NHC 6-14 aryl, C(S)NH-(5- to 14-membered heteroaryl), NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NHC 7-16 aralkyl, NHC 2-6 alkenyl, NHC(O)C 1-6 alkyl, NHC(O)C 7-16 aralkyl, NHC(O)OC 1-6 alkyl, NHC(O)OC 7-16 aralkyl, NHC 3-10 cycloalkyl, NHC 3-10 cycloalkenyl, NH-(3- to 14-membered heterocyclyl), NHC 6-14 aryl, NH-(5- to 14-membered heteroaryl), OH, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 7-16 aralkyl, OC 2-6 alkenyl, OC 3-10 cycloalkyl, OC 3-10 cycloalkenyl, O-(3- to 14-membered heterocyclyl), OC 6-14 aryl, O-(5- to 14-membered heteroaryl), P(O)(OH) 2 , SH, SC 1-6 alkyl, SC 1-6 haloalkyl, SC 7-16 aralkyl, SC 2-6 alkenyl, SC 3-10 cycloalkyl, SC 3-10 cycloalkenyl, S-(3- to 14-membered heterocyclyl), SC 6-14 aryl, S-(5- to 14-membered heteroaryl), S(O)C 1-6 alkyl, S(O)C 1-6 haloalkyl, S(O)C 7-16 aralkyl, S(O)C 2-6 alkenyl, S(O)C 3-10 cycloalkyl, S(O)C 3-10 cycloalkenyl, S(O)-(3- to 14-membered heterocyclyl), S(O)C 6-14 aryl, S(O)-(5- to 14-membered heteroaryl), S(O) 2 C 1-6 alkyl, S(O) 2 C 1-6 haloalkyl, S(O) 2 C 7-166 aralkyl, S(O) 2 C 2-6 alkenyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 C 3-10 cycloalkenyl, S(O) 2 -(3- to 14-membered heterocyclyl), S(O) 2 C 6-14 aryl, S(O) 2 -(5- to 14-membered heteroaryl), S(O) 2 NH 2 , S(O) 2 NH 2 , S(O) 2 NHC 1-6 alkyl, S(O) 2 N(C 1-6 alkyl) 2 , S(O) 2 NHC 7-16 aralkyl, S(O) 2 NHC 2-6 alkenyl, S(O) 2 NHC 3-10 cycloalkyl, S(O) 2 NHC 3-10 cycloalkenyl, S(O) 2 NH-(3- to 14-membered heterocyclyl), S(O) 2 NHC 6-14 aryl, S(O) 2 NH-(5- to 14-membered heteroaryl), SiH 3 , Si(C 1-6 alkyl) 3 , Si(C 7-16 aralkyl) 3 , Si(C 2-6 alkenyl) 3 , Si(C 3-10 cycloalkyl) 3 , Si(C 3-10 cycloalkenyl) 3 , Si-(3- to 14-membered heterocyclyl) 3 , Si(C 6-14 aryl) 3 , Si-(5- to 14-membered heteroaryl) 3 , C 3-10 cycloalkyl, C 3-10 cycloalkenyl, heterocyclyl, C 6-14 aryl, and heteroaryl; and

Ring B 1 is heteroaryl, wherein the heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 7-16 aralkyl, C 2-6 alkenyl, C 2-6 alkynyl, C(O)H, C(O)C 1-6 alkyl, C(O)C 1-6 haloalkyl, C(O)C 7-16 aralkyl, C(O)C 2-6 alkenyl, C(O)C 3-10 cycloalkyl, C(O)C 3-10 cycloalkenyl, C(O)-(3- to 14-membered heterocyclyl), C(O)C 6-14 aryl, C(O)-(5- to 14-membered heteroaryl), C(O)NH 2 , C(O)NHC 1-6 alkyl, C(O)NHC 1-6 haloalkyl, C(O)NHC 7-16 aralkyl, C(O)NHC 2-6 alkenyl, C(O)NHC 3-10 cycloalkyl, C(O)NHC 3-10 cycloalkenyl, C(O)NH-(3- to 14-membered heterocyclyl), C(O)NHC 6-14 aryl, C(O)NH-(5- to 14-membered heteroaryl), C(O)N(C 1-6 alkyl) 2 , C(O)OH, C(O)OC 1-6 alkyl, C(O)OC 1-6 haloalkyl, C(O)OC 7-16 aralkyl, C(O)OC 2-6 alkenyl, C(O)OC 3-10 cycloalkyl, C(O)OC 3-10 cycloalkenyl, C(O)O-(3- to 14-membered heterocyclyl), C(O)OC 6-14 aryl, C(O)O-(5- to 14-membered heteroaryl), C(S)NH 2 , C(S)NHC 1-6 alkyl, C(S)NHC 1-6 haloalkyl, C(S)NHC 7-16 aralkyl, C(S)NHC 2-6 alkenyl, C(S)NHC 3-10 cycloalkyl, C(S)NHC 3-10 cycloalkenyl, C(S)NH-(3- to 14-membered heterocyclyl), C(S)NHC 6-14 aryl, C(S)NH-(5- to 14-membered heteroaryl), NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NHC 7-16 aralkyl, NHC 2-6 alkenyl, NHC(O)C 1-6 alkyl, NHC(O)C 7-16 aralkyl, NHC(O)OC 1-6 alkyl, NHC(O)OC 7-16 aralkyl, NHC 3-10 cycloalkyl, NHC 3-10 cycloalkenyl, NH-(3- to 14-membered heterocyclyl), NHC 6-14 aryl, NH-(5- to 14-membered heteroaryl), OH, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 7-16 aralkyl, OC 2-6 alkenyl, OC 3-10 cycloalkyl, OC 3-10 cycloalkenyl, O-(3- to 14-membered heterocyclyl), OC 6-14 aryl, O-(5- to 14-membered heteroaryl), P(O)(OH) 2 , SH, SC 1-6 alkyl, SC 1-6 haloalkyl, SC 7-16 aralkyl, SC 2-6 alkenyl, SC 3-10 cycloalkyl, SC 3-10 cycloalkenyl, S-(3- to 14-membered heterocyclyl), SC 6-14 aryl, S-(5- to 14-membered heteroaryl), S(O)C 1-6 alkyl, S(O)C 1-6 haloalkyl, S(O)C 7-16 aralkyl, S(O)C 2-6 alkenyl, S(O)C 3-10 cycloalkyl, S(O)C 3-10 cycloalkenyl, S(O)-(3- to 14-membered heterocyclyl), S(O)C 6-14 aryl, S(O)-(5- to 14-membered heteroaryl), S(O) 2 C 1-6 alkyl, S(O) 2 C 1-6 haloalkyl, S(O) 2 C 7-166 aralkyl, S(O) 2 C 2-6 alkenyl, S(O) 2 C 3-10 cycloalkyl, S(O) 2 C 3-10 cycloalkenyl, S(O) 2 -(3- to 14-membered heterocyclyl), S(O) 2 C 6-14 aryl, S(O) 2 -(5- to 14-membered heteroaryl), S(O) 2 NH 2 , S(O) 2 NH 2 , S(O) 2 NHC 1-6 alkyl, S(O) 2 N(C 1-6 alkyl) 2 , S(O) 2 NHC 7-16 aralkyl, S(O) 2 NHC 2-6 alkenyl, S(O) 2 NHC 3-10 cycloalkyl, S(O) 2 NHC 3-10 cycloalkenyl, S(O) 2 NH-(3- to 14-membered heterocyclyl), S(O) 2 NHC 6-14 aryl, S(O) 2 NH-(5- to 14-membered heteroaryl), SiH 3 , Si(C 1-6 alkyl) 3 , Si(C 7-16 aralkyl) 3 , Si(C 2-6 alkenyl) 3 , Si(C 3-10 cycloalkyl) 3 , Si(C 3-10 cycloalkenyl) 3 , Si-(3- to 14-membered heterocyclyl) 3 , Si(C 6-14 aryl) 3 , Si-(5- to 14-membered heteroaryl) 3 , C 3-10 cycloalkyl, C 3-10 cycloalkenyl, heterocyclyl, C 6-14 aryl, and heteroaryl.

2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

Z is —CHR 1 CH 2 —; and

R 1 is —C 1-4 alkyl.

3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring B 1 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted.

4. The compound according to claim 1 , wherein the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C 1-4 alkyl;

Ring A 2 is phenyl or a 5- or 6-membered heteroaryl, wherein the phenyl or 5- or 6-membered heteroaryl is optionally substituted; and

Ring B 2 is a 5-membered heteroaryl, wherein the 5-membered heteroaryl is optionally substituted.

6. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein:

(i) Y 1 is N; or

(ii) Y 2 is N; or

(iii) Y 3 is N; or

(iv) Y 4 is N.

7. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is CH 3 .

8. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein Ring A 2 is phenyl or a 6-membered heteroaryl, wherein the phenyl or 6-membered heteroaryl is optionally substituted with at least one CN substituent.

9. The compound according to claim 5 , or a pharmaceutically acceptable salt thereof, wherein:

X 1 is CR X1 ;

R X1 is H; and

Ring B 2 is triazol-1-yl or tetrazol-1-yl.

10. The compound according to claim 5 , wherein the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof,

wherein:

Ring B 2 is triazol-1-yl or tetrazol-1-yl.

11. The compound according to claim 1 , wherein the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof,

wherein:

Ring A 3 is phenyl or a 6-membered nitrogen-containing heteroaryl, wherein the phenyl or 6-membered nitrogen-containing heteroaryl is optionally substituted; and

W is CH or N.

12. The compound according to claim 11 , or a pharmaceutically acceptable salt thereof, wherein

is formula (A 3 -1):

Q 1 is CR Q1 or N;

Q 2 is CR Q2 or N;

Q 3 is CR Q3 or N;

Q 4 is CR Q4 or N;

R Q1 is H, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 7-16 aralkyl, C(O)C 1-6 alkyl, C(O)-(monocyclic 3- to 8-membered heterocyclyl), C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl) 2 , C(O)OH, C(O)OC 1-6 alkyl, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , NHC 7-16 aralkyl, NHC(O)C 1-6 alkyl, NHC(O)C 7-16 aralkyl, NHC(O)OC 1-6 alkyl, NHC(O)OC 7-16 aralkyl, OH, OC 1-6 alkyl, OC 1-6 haloalkyl, OC 7-16 aralkyl, OC 3-10 cycloalkyl, O-(monocyclic 3- to 8-membered heterocyclyl), C 3-10 cycloalkyl, or a monocyclic 3- to 8-membered heterocyclyl;

R Q2 is H, halogen, or OC 1-6 alkyl;

R Q3 is H, halogen, CN, C 1-6 alkyl, C(O)C 1-6 alkyl, C(O)NHC 1-6 alkyl, C(O)N(C 1-6 alkyl) 2 , C(O)OH, C(O)OC 1-6 alkyl, NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , or OC 1-6 alkyl; and

R Q4 is H or halogen.

13. The compound according to claim 11 , wherein the compound is represented by the following formula:

or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

15. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.