US 2019/0100531 A1Published application

Heterocyclic compound used as fgfr inhibitor

AssigneeHangzhou Innogate Pharma Co., Ltd.

InventorsHancheng ZHANG, Shifeng LIU

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Abstract

A heterocyclic compound is described, which is an inhibitor of FGFR (fibroblast growth factor receptor). Specifically, it is a compound represented by the following formula (I), including an isomer (enantiomer or diastereomer) which may be present, or a pharmaceutically acceptable salt thereof, prodrugs, deuterated derivatives, hydrates, solvates. The definition of each group in the formula (I) is as described in the specification. The compound of the present invention has FGFR inhibitory activity and can be used for preventing or treating a disease associated with FGFR activity or expression.

Claims21

Dependent claims

A compound of formula (I), including possible isomers (enantiomer or diastereomer), or a pharmaceutically acceptable salt, prodrug or deuterated derivative, hydrate, or solvate thereof:

wherein:
T1 is N or CR13;
T2 is N, CR13, or C connected to D1;
wherein each R13 is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, CN, OR5, or NR5R6;
D1 is NR3, O, S, CHR4;
wherein R3 is hydrogen, C1-4 alkyl, or (CH2)p—V—(CH2)qN(R6)C(O)R5;
R4 is hydrogen or C1-4 alkyl;
D2 is C(O)NR4, C(O)O, CHR4, NR4, O, or S;
Ar is aryl or heteroaryl;
each R1 is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-4 alkyl, CN, OR5, SR5, NO2, NR5R6, OCOR5, C(O)R5, C(O)OR5, C(O)NR5R6, N(R6)C(O)NR5R6, N(R6)C(O)R5, S(O)2NHR5, S(O)2R5, or NHS(O)2R5;
m is 0, 1, 2, 3, 4 or 5;
R2 is hydrogen, halogen, C1-4 alkyl, CN, OR5, or NR5R6;
U is NR7 or O;
wherein R7 is hydrogen or C1-4 alkyl;
each p and q is independently 0, 1, 2, 3, or 4;
V is a divalent group, when V is CHR5, C3-8 cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl, p is 0-4, q is 0-4;
when V is CH═CH or C≡C, p is 1-4, q is 1-4;
when V is O or NR15, p is 2-4, q is 2-4;
wherein R15 is hydrogen, C1-4 alkyl, C(O)R5, or S(O)2R5;
each of R5 and R6 is independently hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl;
or R5 and R6 together with the nitrogen atom they attached form a 3- to 8-membered cyclic structure (saturated or partially saturated) which optionally containing 0-2 additional heteroatoms selected from N, O or S;
A is formula (II):
or A is a group selected from the group consisting of:
wherein:
“” represents the attaching point of A to U in formula (I);
“*” indicates a chiral center;
each K, M, P and Q is independently N or CR8;
X is hydrogen, halogen, C1-4 alkyl, CN, OR5, NO2, NR5R6, C(O)OR5, C(O)NR5R6, N(R6)C(O)R5 or S(O)2R5;
each R14 is independently hydrogen, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic, CN, OR5, SR5, NR5R6, C(O)R5, C(O)OR5, C(O)NR5R6, OC(O)R5, NR6C(O)R5, S(O)2R5, ═O, or ═S;
n is 0, 1 or 2;
each a, b, and c is independently 0, 1, 2, or 3;
J is O, S, CR9R10, NR12, or C(O);
E is N or CR11;
G is NR12, O, S, S(O), S(O)2, or CR9R10;
wherein,
each R8 is independently hydrogen, halogen, C1-4 alkyl, CN, OR5, NO2, NR5R6, C(O)OR5, C(O)NR5R6, N(R6)C(O)R5 or S(O)2R5;
each R9 or R10 is independently hydrogen, halogen, or C1-4 alkyl;
R11 is hydrogen, C1-4 alkyl, or OR5;
R12 is hydrogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl, 3- to 8-heterocyclyl, aryl, heteroaryl, C(O)R5, C(O)OR5, C(O)NR5R6, or S(O)2R5;
wherein each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally and each independently substituted with 1-3 substituents, and the substituents are each independently selected from halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, NO2, OR5, SR5, NR5R6, C(O)R5, C(O)OR5, C(O)NR5R6, NC(O)NR5R6, N(R6)C(O)R5, or S(O)2R5;
unless otherwise specified, the above aryl group is aryl group having 6 to 12 carbon atoms;
and the heteroaryl group is 5- to 15-membered heteroaryl group.

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Dependencies are inferred from the claim text.

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Abstract

A compound of formula (I), including possible isomers (enantiomer or diastereomer), or a pharmaceutically acceptable salt, prodrug or deuterated derivative, hydrate, or solvate thereof:

wherein:
T1 is N or CR13;
T2 is N, CR13, or C connected to D1;
wherein each R13 is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, CN, OR5, or NR5R6;
D1 is NR3, O, S, CHR4;
wherein R3 is hydrogen, C1-4 alkyl, or (CH2)p—V—(CH2)qN(R6)C(O)R5;
R4 is hydrogen or C1-4 alkyl;
D2 is C(O)NR4, C(O)O, CHR4, NR4, O, or S;
Ar is aryl or heteroaryl;
each R1 is independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halogenated C1-4 alkyl, CN, OR5, SR5, NO2, NR5R6, OCOR5, C(O)R5, C(O)OR5, C(O)NR5R6, N(R6)C(O)NR5R6, N(R6)C(O)R5, S(O)2NHR5, S(O)2R5, or NHS(O)2R5;
m is 0, 1, 2, 3, 4 or 5;
R2 is hydrogen, halogen, C1-4 alkyl, CN, OR5, or NR5R6;
U is NR7 or O;
wherein R7 is hydrogen or C1-4 alkyl;
each p and q is independently 0, 1, 2, 3, or 4;
V is a divalent group, when V is CHR5, C3-8 cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl, p is 0-4, q is 0-4;
when V is CH═CH or C≡C, p is 1-4, q is 1-4;
when V is O or NR15, p is 2-4, q is 2-4;
wherein R15 is hydrogen, C1-4 alkyl, C(O)R5, or S(O)2R5;
each of R5 and R6 is independently hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic, aryl, or heteroaryl;
or R5 and R6 together with the nitrogen atom they attached form a 3- to 8-membered cyclic structure (saturated or partially saturated) which optionally containing 0-2 additional heteroatoms selected from N, O or S;
A is formula (II):
or A is a group selected from the group consisting of:
wherein:
“” represents the attaching point of A to U in formula (I);
“*” indicates a chiral center;
each K, M, P and Q is independently N or CR8;
X is hydrogen, halogen, C1-4 alkyl, CN, OR5, NO2, NR5R6, C(O)OR5, C(O)NR5R6, N(R6)C(O)R5 or S(O)2R5;
each R14 is independently hydrogen, halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic, CN, OR5, SR5, NR5R6, C(O)R5, C(O)OR5, C(O)NR5R6, OC(O)R5, NR6C(O)R5, S(O)2R5, ═O, or ═S;
n is 0, 1 or 2;
each a, b, and c is independently 0, 1, 2, or 3;
J is O, S, CR9R10, NR12, or C(O);
E is N or CR11;
G is NR12, O, S, S(O), S(O)2, or CR9R10;
wherein,
each R8 is independently hydrogen, halogen, C1-4 alkyl, CN, OR5, NO2, NR5R6, C(O)OR5, C(O)NR5R6, N(R6)C(O)R5 or S(O)2R5;
each R9 or R10 is independently hydrogen, halogen, or C1-4 alkyl;
R11 is hydrogen, C1-4 alkyl, or OR5;
R12 is hydrogen, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl, 3- to 8-heterocyclyl, aryl, heteroaryl, C(O)R5, C(O)OR5, C(O)NR5R6, or S(O)2R5;
wherein each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroaryl is optionally and each independently substituted with 1-3 substituents, and the substituents are each independently selected from halogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-8 cycloalkyl, 3- to 8-membered heterocyclic group, aryl, heteroaryl, CN, NO2, OR5, SR5, NR5R6, C(O)R5, C(O)OR5, C(O)NR5R6, NC(O)NR5R6, N(R6)C(O)R5, or S(O)2R5;
unless otherwise specified, the above aryl group is aryl group having 6 to 12 carbon atoms;
and the heteroaryl group is 5- to 15-membered heteroaryl group.

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