Granted Patent B2

US 10,023,571 · App. 15/254,071 · Granted Jul 17, 2018

Abstract

Claims (40)

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X is ═C(R 6 )—;

Y is ═N—;

Ring A is phenyl; a 5-6 membered partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered bicyclic heteroaryl ring having 2-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each of R 1 and R 1′ is independently hydrogen, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R; or

R 1 and R 1′ are taken together with their intervening atoms to form an optionally substituted 3-7 membered spiro-fused ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each R 2 is independently an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

R 3 is Cy 1 ; wherein R 3 is substituted with n instances of R 8 ;

R 5 is halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , —N(R)S(O) 2 R, and Cy 2 ; wherein R 5 is substituted with p instances of R 9 ; or when Ring A is partially unsaturated, L′R 5 , taken together, may also be absent;

each of Cy 1 and Cy 2 is independently phenyl; a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 6-12 membered bicyclic carbocyclic ring; a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur;

each instance of R 6 is independently hydrogen, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

each instance of R 7 and R 8 is independently oxo, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

each instance of R 9 is independently oxo, C 1-6 hydroxyaliphatic, —R 2 , halogen, —CN, —NO 2 , —OR, —SR, —NR 2 , —S(O) 2 R, —S(O) 2 NR 2 , —S(O)R, —C(O)R, —C(O)OR, —C(O)NR 2 , —C(O)N(R)OR, —OC(O)R, —OC(O)NR 2 , —N(R)C(O)OR, —N(R)C(O)R, —N(R)C(O)NR 2 , or —N(R)S(O) 2 R;

L 1 is a covalent bond or a C 1-6 bivalent saturated or unsaturated, straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —N(R)S(O) 2 —, —S(O) 2 N(R)—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —S—, —S(O)— or —S(O) 2 —;

m is 0-2;

n is 0-4;

p is 0-3; and

each R is independently hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocyclic having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or:

two R groups on the same nitrogen are taken together with their intervening atoms to form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition to the nitrogen, independently selected from nitrogen, oxygen, and sulfur.

2. The compound of claim 1 of formula II:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 selected from formulas VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VI-g, VI-h, VI-i, VI-j, VI-k, VI-l, VI-m, VI-n, VI-o, VI-p, VI-s, VI-t, VI-u, VI-v, VI-w VI-x, VI-y, VI-z, or VI-aa:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein L 1 is a covalent bond.

5. The compound of claim 1 , wherein L 1 is —C(O)—.

6. The compound of claim 1 , wherein R 3 is selected from:

7. The compound of claim 1 , wherein R 3 (R 8 ) n , taken together, is selected from:

8. The compound of claim 1 , wherein R 5 is Cy 2 .

9. The compound of claim 1 , wherein R 5 is selected from:

10. The compound of claim 1 , wherein R 5 (R 9 ) p , taken together, is selected from:

11. The compound of claim 1 , wherein at least one R 8 is halogen, —CN, or hydroxymethyl.

12. The compound of claim 1 , wherein Ring A is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

13. The compound of claim 12 , wherein Ring A is pyrazolyl.

14. The compound of claim 1 of formula VIII-b:

or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14 , wherein n is 2-3.

16. The compound of claim 1 wherein said compound is selected from

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

Assignments (14)

Cited By (2)

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