Granted Patent B2

US 11,731,977 · App. 17/485,892 · Granted Aug 22, 2023

Inventors: Glen Robert Rennie (Somerville, MA); Rajesh R. Iyengar (West Newton, MA); Thomas Wai-Ho Lee (Lexington, MA); Paul Allan Renhowe (Sudbury, MA); Joon Jung (Newton, MA); Kim Tang (Belmont, MA)

Assignee: Cyclerion Therapeutics, Inc.

C07D487/04A61K31/437A61K31/4985A61K31/52C07D471/04C07D473/00

Abstract

Claims (79)

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,

wherein:

the core formed by rings E and A along with the substituents (J c ) p is represented by the following formula:

wherein the C atom with a symbol * represents the attachment point to the ring containing G, Z, and Q; and the C atom with a symbol ** represents the point of attachment of the 2 instances of J;

W is either

i) absent, with J B connected directly to the carbon atom bearing two J groups, each J is independently selected from hydrogen or methyl, n is 1 and J B is a C 1-7 alkyl chain optionally substituted by up to 9 instances of fluorine; or

ii) a ring B that is a phenyl, a C 3-7 cycloalkyl ring or a 5 or 6-membered heteroaryl ring, containing 1 or 2 ring nitrogen atoms;

wherein when ring B is the phenyl or 5 or 6-membered heteroaryl ring; each J is independently selected from hydrogen or methyl; n is 0 or 1; and each J B is independently selected from halogen, —CN, a C 1-6 aliphatic, —OR B or a C 3-8 cycloaliphatic ring; and

wherein when ring B is the C 3-7 cycloalkyl ring; each J is hydrogen; n is 0 or 1 and each J B is independently selected from halogen, —CN, a C 1-6 aliphatic or —OR B1 ;

wherein each J B that is a C 1-6 aliphatic and each J B that is a C 3-8 cycloaliphatic ring is optionally and independently substituted with up to 3 instances of R 3 ;

each R B is independently selected from a C 1-6 aliphatic or a C 3-8 cycloaliphatic ring; said R B optionally and independently substituted with up to 3 instances of R 3a ;

each R B1 is independently selected from hydrogen, a C 1-6 aliphatic or a C 3-8 cycloaliphatic ring; wherein each of said C 1-6 aliphatic and each of said C 3-8 cycloaliphatic ring is optionally and independently substituted with up to 3 instances of R 3b ;

each R 3 , R 3a and R 3b is, in each instance, independently selected from halogen, —CN, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) or —O(C 1-4 haloalkyl);

each J C is independently selected from hydrogen, halogen, C 1-4 aliphatic, C 1-4 alkoxy or —CN; wherein each said C 1-4 aliphatic and C 1-4 alkoxy is optionally and independently substituted by up to 3 instances of C 1-4 alkoxy, C 1-4 haloalkoxy, —OH or halogen;

Q, G, and Z are each independently N, S, or O, wherein at least two of Q, G, and Z are N;

q is 0, 1, or 2;

R 10 is C 1-6 alkyl optionally and independently substituted with 0-3 occurrences of R 15 , phenyl optionally and independently substituted with 0-3 occurrences of R 15 , 5- or 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 15 , C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 15 or 3-8 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 15 ; wherein each of said 5- to 6-membered heteroaryl ring and each of said 3-8 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;

R 11 is H, —NR a2 R b2 , —C(O)NR a2 R b2 , —C(O)R 15a , —SO 2 R b2 , —SR b2 , halo, —OCF 3 , —CN, hydroxyl, C 2-6 alkenyl optionally and independently substituted with 0-2 occurrences of R b2 , C 2-6 alkynyl optionally and independently substituted with 0-2 occurrences of R b2 ; C 1-6 alkyl optionally and independently substituted with 0-5 occurrences of R 15 , C 1-6 alkoxy optionally and independently substituted with 0-5 occurrences of R 15 , phenyl optionally and independently substituted with 0-3 occurrences of R 15 , 5- to 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 15 , C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 15 or 3-8 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 15 ; wherein each of said 5- to 6-membered heteroaryl and each of said 3-8 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S; or

when R 10 is a substituent of Z, R 10 and R 11 , taken together with Z and the carbon to which R 11 is attached, form a 3-10 membered heterocyclic ring optionally and independently substituted with 0-3 occurrences of R 15 ; wherein each of said 3-10 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;

R 15 is halo, —OR b2 , —SR b2 , —NR a2 R b2 , —C(O)R b2 , —C(O)NR a2 R b2 , —NR b2 C(O)OR b2 , —OC(O)NR a2 R b2 , C 2-4 alkenoxy, C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R 18 , phenyl optionally and independently substituted with 0-3 occurrences of R 18 , 5- or 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 18 or 3-10 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 18 ; wherein each of said 5- or 6-membered heteroaryl ring and each of said 3-10 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;

R 15a is C 3-8 cycloalkyl optionally and independently substituted with 0-3 occurrences of R18, phenyl optionally and independently substituted with 0-3 occurrences of R 18 , 5- or 6-membered heteroaryl optionally and independently substituted with 0-3 occurrences of R 18 or 3-10 membered heterocyclyl optionally and independently substituted with 0-3 occurrences of R 18 ; wherein each of said 5- or 6-membered heteroaryl ring and each of said 3-10 membered heterocyclyl contains up to 3 ring heteroatoms independently selected from N, O or S;

each R 18 is independently selected from halo, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl or phenyl;

R a2 is hydrogen, —C(O)R b2 , C 1-6 alkyl or C 1-6 haloalkyl; and

R b2 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.

2. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is a ring B and the compound is one of Formula BIB, or a pharmaceutically acceptable salt thereof:

3. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein ring B is phenyl.

4. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein each J B is independently selected from halogen, a C 1-4 alkyl, —OR B and —OR B1 .

5. A compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein n is 1 and each J B is a halogen atom.

6. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is absent and the compound is one of Formula IIA, or a pharmaceutically acceptable salt thereof:

wherein J B is a C 1-7 alkyl chain optionally substituted by up to 9 instances of fluorine.

7. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein J B is a C 1-4 alkyl chain, optionally substituted by up to 5 instances of fluorine.

8. A compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 11 is H or C 1-6 alkyl optionally and independently substituted with 0-5 occurrences of R 15 ; and R 15 is halo in each instance.

9. A compound according to claim 6 , wherein R 11 is —CF 3 .

10. A compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein q is 0.

11. A compound according to claim 7 , or a pharmaceutically acceptable salt thereof, wherein each instance of J C is hydrogen.

12. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is one of Formula III, or a pharmaceutically acceptable salt thereof, or any of its tautomers thereof:

13. A compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 11 is H or C 1-6 alkyl optionally and independently substituted with 0-5 occurrences of R 15 ; and R 15 is halo in each instance.

14. A compound according to claim 12 , wherein R 11 is —CF 3 .

15. A compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein q is 0.

16. A compound according to claim 12 , or a pharmaceutically acceptable salt thereof, wherein each instance of J C is hydrogen.

17. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from those listed in the table below:

I-1

I-2

I-3

I-4

I-5

I-6

I-7

I-12

I-13

I-14

I-31

I-32

I-38

I-39

I-41

I-42

I-47

I-48

I-50

I-51

I-53

I-54

I-56

I-57

I-58

I-59

I-60

I-62

I-63

I-64

I-65

I-66

I-67

I-68

I-70

I-71

or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient or carrier.

Assignments (4)

Continuity (8)