US 11,028,064 B2 · Tricyclic heterocyclic derivatives and uses thereof

Abstract

Disclosed are tricyclic heterocyclic compounds having kinase inhibitory activity, pharmaceutical compositions and kits comprising the compounds, and use of the compounds in the treatment of or in medicaments for the treatment of various diseases and conditions. In particular, disclosed are tricyclic heterocyclic compounds of the formula (I) having CSF-1R (c-FMS kinase) inhibitory activity and their use in the treatment of various diseases and conditions, such as those mediated by CSF-1R, including proliferative or neoplastic diseases and conditions, including cancers, and bone, inflammatory, and autoimmune diseases and conditions.

A compound of formula (I):

wherein:
X is NR4, O, S, SO, SO2, Se or Te and R2 is G at any one of positions 2 to 4;
or
X is NG1 and R2 is H, D, NR6R7, OR6, SR8, halogen, CF3, OCF3, CN, NR6COR8, NR6S2R8, or C1-4alkyl optionally substituted with one or more independently selected Ra;
Y is CHR6, CO, CHR6NR5, CHR6O, CHR6S, CHR6SO2, CONR5, NR5, NR5CO, NR5SO2, O, OCHR6, S, SO, SO2, SCHR6, SO2CHR6, or SO2NR5;
Z is W or —W1—Y1—W2;
R1 and R3 are each independently H, D, NR6R7, OR6, SR8, halogen, CF3, OCF3, CN, NR6COR8, NR6SO2R8, or C1-4alkyl optionally substituted with one or more independently selected Ra;
R4 is H or C1-6alkyl optionally substituted with one or more independently selected Rb;
R5 is H or C1-4alkyl optionally substituted with one or more independently selected Rc;
R6 and R7 at each instance are each independently H or unsubstituted C1-4alkyl;
R8 at each instance is independently unsubstituted C1-4alkyl;
G is -J1-L1-NR9aR10a, -J1-L2-NR9bR10b, -J1-L3CR11R12R13, -L10-NR9aR10a, -L20-NR9bR10b, or -L30-CR11R12R13;
G1 is -L1-NR9aR10a, -L2-NR9bR10b, or -L3-cR11R12R13;
J1 is O, NR6S, —(C1-3alkylene)O—*, —(C1-3alkylene)NR6—*, or —(C1-3alkylene)S—*, wherein each alkylene is unsubstituted and wherein * denotes the bond to L1, L2, or L3;
L1 and L2 are each independently C2-6alkylene, —C2-3alkylene-J2-C2-3alkylene-*, —(C1-3alkylene)a-A-(C1-3alkylene)b-*, —C2-3alkylene-J2-(C1-3alkylene)a-A-(C1-3alkylene)b-*, or —(C1-3alkylene)a-A-(C1-3alkylene)b-J2C2-3alkylene-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to NR9aR10a or NR9bR10b;
L3 is a bond, C1-6alkylene, —C2-6alkylene-J2-*, —C2-3alkylene-J2-C1-3alkylene-*, —(C1-3alkylene)a-A-(C1-3alkylene)b-*, —C2-3alkylene-J2-(C1-3alkylene)a-A-(C1-3alkylene)b-*, or —(C1-3alkylene)a-A-(C1-3alkylene)b-J2-(C1-3alkylene)-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to CR11R12R13;
L10 and L20 are each independently C1-6alkylene, —C1-3alkylene-J2-C2-3alkylene-*, —(C1-3alkylene)a-A-(C1-3alkylene)b-*, —C1-3alkylene-J2-(C1-3alkylene)a-A-(C1-3alkylene)b-*, or —(C1-3alkylene)a-A-(C1-3alkylene)b-J2-C2-3alkylene-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to NR9aR10a or NR9bR10b;
L30 is C1-6alkylene, —C1-6alkylene-J2-*, —C1-3alkylene-J2-C1-3alkylene-*, —(C1-3alkylene)a-A-(C1-3alkylene)b-*, —C1-3alkylene-J2-(C1-3alkylene)a-A-(C1-3alkylene)b-*, or —(C1-3alkylene)a-A-(C1-3alkylene)b-J2-(C1-3alkylene)c-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to CR11R12R13;
A is 3 to 7-membered cycloalkylene optionally substituted with one or more independently selected Rd;
J2 is O, NR6, or S;
a, b, and c are each independently 0 or 1;
R9a and R10a are each independently H, unsubstituted C1-6alkyl, or unsubstituted 3 to 10-membered cycloalkyl;
R9b and R10b together with the nitrogen atom to which they are attached form a 4 to 10-membered heterocyclyl or 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected Rg;
R11 and R12 together with the carbon atom to which they are attached form a 4 to 10-membered heterocyclyl comprising at least one ring nitrogen atom, optionally substituted with one or more independently selected Rg;
and R13 is H, C1-4alkyl optionally substituted with one or more independently selected Rh, or the second bond of a double bond between R11 or R12 and the carbon atom to which they are attached;
or
R11 and R12 together with the carbon atom to which they are attached form a 5 to 10-membered heteroaryl comprising at least one ring nitrogen atom, optionally substituted with one or more independently selected Rg;
and R13 is the second bond of a double bond between R11 or R12 and the carbon atom to which they are attached;
W is 6 to 10-membered aryl or 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected Ri;
W1 is phenylene or 5 or 6-membered hetereoarylene, optionally substituted with one or more independently selected Rx;
Y1 is C1-6alkylene-J4-*, —(C1-3alkylene)-J4-*, —(C1-3alkylene)-J5-(C1-3alkylene)-*, -J5-(C1-3alkylene)-*, or -J6-C1-3alkylene-J7-*, wherein each alkylene is unsubstituted and wherein * denotes the bond to W2;
J4 is O, NR14, S, NR15CO, CONR14, NR15CONR14, OCONR14, or NR15COO;
J5 is O, NR15, S, NR15CO, CONR15, NR15CONR15, OCONR15, or NR15COO;
J6 is O, NR15, or S;
J7 is O, NR14, S, NR15CO, or CONR14;
R14 and R15 at each instance are each independently H or C1-3alkyl optionally substituted with one or more independently selected Rj;
W2 is:
(a) 3 to 10-membered cycloalkyl or 4 to 10-membered heterocyclyl, optionally substituted with one or more independently selected Rm, or
(b) 6 to 10-membered aryl or 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected Rn;
or R14 and W2 together with the nitrogen atom to which they are attached form:
(a) a 4 to 10-membered heterocyclyl, optionally substituted with one or more independently selected Rm, or
(b) a 5 to 10-membered heteroaryl, optionally substituted with one or more independently selected Rn;
Ra, Rb, Rc, and Rh at each instance are each independently selected from F, OCF3, and O(unsubstituted C1-4alkyl);
Rd and Rg at each instance are each independently selected from D, NR6R7, OR6, SR8, halogen, CF3, OCF3, CN, SO2R8, NR6COR8, NR6SO2R8, and C1-4alkyl optionally substituted with one or more substituents independently selected from F, OCF3, and O(unsubstituted C1-4alkyl);
Ri, Rx, and Rn at each instance are each independently selected from D, NR6R7, OR6, SR8, halogen, CF3, OCF3, CN, SO2R8, and C1-4alkyl optionally substituted with one or more substituents independently selected from F, OCF3, and O(unsubstituted C1-4alkyl);
Rj at each instance is independently selected from F and D;
Rm at each instance is independently selected from D, NR6R7, OR6, SR8, F, CF3, OCF3, CN, SO2R8, and C1-4alkyl optionally substituted with one or more substituents independently selected from F, OCF3, and O(unsubstituted C1-4alkyl);
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

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Tricyclic heterocyclic derivatives and uses thereof

Life of this patent

Tricyclic heterocyclic derivatives and uses thereof

Life of this patent

Abstract

Claims18