IP Library › Granted Patent US 10,138,256

Granted Patent B2

US 10,138,256 · App. 14/760,697 · Granted Nov 27, 2018

MK2 inhibitors and uses thereof

Inventors: Matthew David Alexander (Boston, MA); Joseph John McDonald (Sudbury, MA); Yike Ni (Lexington, MA); Deqiang Niu (Lexington, MA); Russell C. Petter (Stow, MA); Lixin Qiao (Andover, MA); Juswinder Singh (Southborough, MA); Tao Wang (Sudbury, MA); Zhendong Zhu (Westborough, MA)

Assignee: Celgene CAR LLC

C07D519/00 A61K47/48246 C07D213/74 C07D213/75 C07D401/04 C07D401/12 C07D413/04 C07D413/12 C07D471/04 C07D471/14 C07D471/20 C07D487/04 C07D487/10 C07D495/04 C07D495/14 C12N9/12 C12N9/96 C12N9/99 G01N33/573 C12Y207/11001 G01N2333/91205 G01N2458/00 G01N2500/04 G01N2500/20

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Quick Facts

Patent No.: US 10,138,256
App. No.: 14/760,697
Granted: Nov 27, 2018
Kind: B2

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Abstract

The present invention provides compounds, compositions thereof, and methods of using the same.

Claims (103)

1. A conjugate comprising a MK2 kinase, having a cysteine residue, Cys140, wherein the Cys140 is covalently, and irreversibly, bonded to an inhibitor, such that inhibition of the kinase is maintained;

wherein said conjugate is of formula A:

Cys140-modifier-inhibitor moiety A

wherein the inhibitor moiety is a moiety that binds in the active site of the MK2 kinase and comprises

wherein

is attached to the modifier; wherein

is an optionally substituted group selected from

a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Y 1 is CR 2 or N;

q is 0-6;

each R 2 is independently —R, halogen, —OR, —SR, —CN, —NO 2 —SO 2 NR, —SO 2 R, —SOR, —C(O)R, —CO 2 R, —C(O)N(R) 2 , —NRC(O)R, —NRC(O)OR, —NRC(O)N(R) 2 , —NRSO_A, or —N(R) 2 ;

each R is independently hydrogen or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

two R groups on the same nitrogen are taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclic ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 4-7 membered heteroaryl ring having 0-4 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

T is a covalent bond, —O—, —S—, —N(R)—, —C(O)—, —OC(O)—, —C(O)O—, —C(O)N(R)—, —N(R)C(O)—, —N(R)C(O)N(R)—, —S(O)—, —SO 2 —, —SO 2 N(R)—, —N(R)SO 2 —, or —N(R)SO 2 N(R)—; and

the modifier is selected from:

2. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring A is an optionally substituted group selected from

or a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Y 2 is CR′ or N;

each R′ is independently hydrogen, halo, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 3 is an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 4 is an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

3. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring B is an optionally substituted group selected from

Y 2 is CR′ or N;

R 6 is hydrogen, an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 7 is hydrogen, an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or R 6 and R 7 are taken together to form a C 2-6 alkylene;

R 8 is hydrogen, an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 9 is hydrogen, an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or R 8 and R 9 are taken together with the carbon atom to which they are attached to form a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group;

provided that when Y 1 is CH; Y 2 is CH; each of R 6 , R 7 , R 8 , R 9 , and R a is hydrogen; and T is a covalent bond, then at least one of (R 2 ) q is other than hydrogen.

4. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring B′ is

or an optionally substituted group selected from a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

Y 2 is CR′ or N;

or R 6 and R 7 are taken together to form a C 2-6 alkylene or C 2-6 alkenylene;

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

5. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring C is an optionally substituted group selected from

Ring C′ is

or absent;

wherein if Ring C′ is absent, then T is attached to the benzo ring para to S;

Y 2 is CR′ or N;

R 5 is hydrogen, an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

6. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring C″ is an optionally substituted group selected from

Y 2 is CR′ or N;

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

7. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring D is an optionally substituted group selected from a fused 5-6 membered monocyclic heteroaryl ring having 0-2 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a fused 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 additional heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Ring E is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring which is optionally bridged, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

8. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring F is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 10 is hydrogen, an optionally substituted group selected from C 1 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 11 is hydrogen, an optionally substituted group selected from C 1 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

or R 10 and R 11 are taken together with the carbon atom to which they are attached to form a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 1 or 2; and

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

9. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring F′ is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Y 2 is CR′ or N;

R 11 is hydrogen, an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 1 or 2; and

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

10. The conjugate of claim 1 , wherein said conjugate is of formula:

wherein:

Ring G is an optionally substituted group selected from phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated, partially unsaturated or aryl ring which is optionally bridged, an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

Y 2 is CR′ or N;

R 12 is hydrogen, an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 4-7 membered heterocylic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R a is independently hydrogen or an optionally substituted C 1-6 aliphatic group.

11. The conjugate of claim 1 , wherein the modifier is:

12. The conjugate of claim 1 , wherein the modifier is:

Assignments (5)

NUNC PRO TUNC ASSIGNMENT Recorded May 3, 2023

From: CELGENE CAR LLC

To: BRISTOL-MYERS SQUIBB COMPANY

Reel/Frame 063526/0959 →

MERGER AND CHANGE OF NAME Recorded Feb 16, 2017

From: CELGENE AVILOMICS RESEARCH, INC.; CELGENE CAR LLC

To: CELGENE CAR LLC

Reel/Frame 041738/0041 →