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US 2017/0247374 A1Published application
CaMKII INHIBITORS AND USES THEREOF
AssigneeAllosteros Therapeutics, Inc.
InventorsDaniel Emil Levy, Howard Schulman, Bheema Rao Paraselli, Nangunoori Sampath Kumar, Brahmaiah Dabbugoddu, Chundru Balasubramanyam
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Abstract
The present invention provides compounds useful as inhibitors of Ca2+/calmodulin-dependent protein kinase (CaMKII), compositions thereof, and methods of using the same.
Claims19
A compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is an acyclic group or a 5-membered or 6-membered heteroaryl group selected from the list of structures consisting of
- each of R2, R3, R4, R5, R6 and R7 is independently selected from the group consisting of hydrogen, halogen, —CN, —CF3, —OR, —NR2, —NO2, —COOR, —CONR2, and —R;
- each A is independently selected from the group consisting of a covalent bond, an optionally substituted methylene, an optionally substituted cis ethylene, an optionally substituted trans ethylene, an acetylene, C(O), S(O) and S(O)2;
- wherein, if one A is an optionally substituted methylene, an optionally substituted cis ethylene, an optionally substituted trans ethylene, an acetylene, C(O), S(O) or S(O)2, the other must be a covalent bond or an optionally substituted methylene;
- R8 is selected from the group consisting of hydrogen, NH2, guanidino, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- each W is independently N or CR9;
- each X independently N or CR10;
- Y is O, S or NR11;
- Z is O, S or NR12;
- R9 is selected from the group consisting of hydrogen, L-R13, NH2, guanidino, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- wherein, when one R9 group is present, R9 cannot be hydrogen and when two R9 groups are present, one must be hydrogen and the other must not be hydrogen;
- each R10 is independently selected from the group consisting of hydrogen, halogen, —CN, —CF3, —OR, —NR2, —NO2, —COOR, —CONR2, and —R;
- R11 is hydrogen, NH2, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- R12 is hydrogen or optionally substituted C1-6 aliphatic;
- L is a covalent bond or a straight or branched C1-6 aliphatic group, wherein one or more methylene groups are independently and optionally replaced by —NR14— or —O—;
- R13 is selected from the group consisting of NH2, guanidino, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- each R14 is independently hydrogen or C1-3 aliphatic;
- and
- each R is independently hydrogen or optionally substituted C1-6 aliphatic.
17 more elements
A method of synthesizing a compound of the formula I-a:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is an acyclic group or a 5-membered or 6-membered heteroaryl group selected from the list of structures consisting of
- each of R2, R3, R4, R5, R6 and R7 is independently selected from the group consisting of hydrogen, halogen, —CN, —CF3, —OR, —NR2, —NO2, —COOR, —CONR2, and —R;
- each A is independently selected from the group consisting of a covalent bond, an optionally substituted methylene, an optionally substituted cis ethylene, an optionally substituted trans ethylene, an acetylene, C(O), S(O) and S(O)2;
- wherein, if one A is an optionally substituted methylene, an optionally substituted cis ethylene, an optionally substituted trans ethylene, an acetylene, C(O), S(O) or S(O)2, the other must be a covalent bond or an optionally substituted methylene;
- R8 is selected from the group consisting of hydrogen, NH2, guanidino, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- each W is independently N or CR9;
- each X independently N or CR10;
- Y is O, S or NR11;
- Z is O, S or NR12;
- R9 is selected from the group consisting of hydrogen, L-R13, NH2, guanidino, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- wherein, when one R9 group is present, R9 cannot be hydrogen and when two R9 groups are present, one must be hydrogen and the other must not be hydrogen;
- each R10 is independently selected from the group consisting of hydrogen, halogen, —CN, —CF3, —OR, —NR2, —NO2, —COOR, —CONR2, and —R;
- R11 is hydrogen, NH2, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- R12 is hydrogen or optionally substituted C1-6 aliphatic;
- L is a covalent bond or a straight or branched C1-6 aliphatic group, wherein one or more methylene groups are independently and optionally replaced by —NR14— or —O—;
- R13 is selected from the group consisting of NH2, guanidino, 4-7 membered optionally substituted saturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, and 5-6 membered heteroaromatic ring having 1-2 heteroatoms independently selected from sulfur, nitrogen and oxygen;
- each R14 is independently hydrogen or C1-3 aliphatic;
- and
- each R is independently hydrogen or optionally substituted C1-6 aliphatic;
- comprising:
- 1) reacting a compound of the formula:
- wherein R5 and R6 are defined as above;
- with a compound selected from the list of structures consisting of:
- wherein
- R13 is selected from the list consisting of hydrogen, boronic acid, boronic ester, cuprate, MgBr, MgCl, MgI, Li, Na, ZnBr, ZnCl and ZnI;
- wherein any of R8, R9 and R11 may be modified with a protecting group;
- and
- 2) removing a protecting group.
26 more elements
Dependencies are inferred from the claim text.