RU2021101375A

RU2021101375A - HETEROCYCLIC COMPOUNDS AS TRK INHIBITORS

Info

Publication number: RU2021101375A
Application number: RU2021101375A
Authority: RU
Inventors: Норман Сянлун Кун; Чао ЧЖОУ; Чжисян ЧЖЭН
Original assignee: Бэйджинг Иннокэйр Фарма Тек Ко., Лтд.
Priority date: 2018-06-25
Filing date: 2019-06-25
Publication date: 2022-07-25

Claims

1. The compound shown in formula I and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts,

I

wherein L ₁ is selected from -NR ⁶ C(O)-, -NR ⁶ CON(R ⁷ )-, -NR ⁶ S(O) _m - and -NR ⁶ S(O) _m N(R ⁷ )-, in which NR ⁶ is connected to a nitrogen-containing heteroaryl substituted with R ¹ , R ² , R ³ ; preferably L ₁ is selected from -NR ⁶ C(O)- and -NR ⁶ CON(R ⁷ )-, in which NR ⁶ is connected to a nitrogen-containing heteroaryl substituted with R ¹ , R ² , R ³ ; most preferably L ₁ is selected from NR ⁶ CON(R ⁷ )-, in which NR ⁶ is connected to a nitrogen-containing heteroaryl substituted with R ¹ , R ² , R ³ ;

L ₂ is selected from C1-C8 alkylene, C2-C8 alkenylene, C2-C8 alkynylene and C3-C8 cyclylene, wherein alkylene, alkenylene, alkynylene and cyclylene may be optionally substituted with one or more G1; preferably L ₂ is selected from C1-C6 alkylene and C2-C6 alkenylene, which may be optionally substituted with one or more G1; more preferably L ₂ is selected from C1-C4 alkylene, which may be optionally substituted with one or more G1;

L ₃ is selected from a single bond, -O- and -N(R ^x )-; preferably L ₃ is selected from a single bond and -O-; most preferably L ₃ is -O-;

each R ¹ , R ² , R ³ is independently selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, formyl, -NR ⁸ R ⁹ , -C(O) R ¹⁰ , carboxyl, alkenyl, alkynyl, -OR ¹⁰ , -OC(O)NR ⁸ R ⁹ , -C(O)OR ¹⁰ , -C(O)NR ⁸ R ⁹ , -NR ¹¹ C(O)R ¹⁰ , -NR ¹¹ C(O)NR ⁸ R ⁹ , -S(O)mR ¹⁰ , -NR ¹¹ S(O)mR ¹⁰ , -SR ¹⁰ , -S(O)mNR ⁸ R ⁹ and -NR ¹¹ S( O)mNR ⁸ R ⁹ , wherein the alkyl, cyclyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more substituents selected from halo, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, -OR ¹² , -NR ¹³ R ¹⁴ , -OC(O)NR ¹³ R ¹⁴ , -C(O)OR ¹² , -C(O)R ¹² , -C(O)NR ¹³ R ¹⁴ , -NR ¹⁵ C(O)R ¹² , -NR ¹⁵ C(O)NR ¹³ R ¹⁴ , -S(O)mR ¹² , -NR ¹⁵ S(O)mR ¹² , -SR ¹² , -S(O)mNR ¹³ R ¹⁴ and -NR ¹⁵ S (O)mNR ¹³ R ¹⁴ ; preferably both R ² and R ³ are hydrogen; more preferably all of R ¹ , R ² , R ³ are hydrogen;

R ⁴ is selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, formyl, -C(O)R ¹⁰ , carboxyl, alkenyl, alkynyl, -OR ¹⁰ , - NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ , -C(O)OR ¹⁰ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ¹⁰ , -NR ¹⁰ C(O) NR ⁸ R ⁹ , -S(O)mR ¹⁰ , -NR ⁸ S(O)mR ¹⁰ , -SR ¹⁰ , -S(O)mNR ⁸ R ⁹ and -NR ¹⁰ S(O)mNR ⁸ R ⁹ ; preferably R ⁴ is selected from hydrogen, halogen; more preferably R ⁴ is hydrogen or fluoro;

R ⁵ is selected from hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, formyl, -C(O)R ¹⁰ , carboxyl, alkenyl, alkynyl, -OR ¹⁰ , - NR ⁸ R ⁹ , -OC(O)NR ⁸ R ⁹ , -C(O)OR ¹⁰ , -C(O)NR ⁸ R ⁹ , -NR ⁸ C(O)R ¹⁰ , -NR ¹⁰ C(O) NR ⁸ R ⁹ , -S(O)mR ¹⁰ , -NR ⁸ S(O)mR ¹⁰ , -SR ¹⁰ , -S(O)mNR ⁸ R ⁹ and -NR ¹⁰ S(O)mNR ⁸ R ⁹ ; preferably R ⁵ is selected from hydrogen, halo, C1-C6 alkyl and C3-C6 cyclyl; more preferably R ⁵ is selected from hydrogen, halo, C1-C4 alkyl and C3-C6 cyclyl; in addition, preferably R ⁵ is selected from hydrogen and halogen; most preferably R ⁵ is fluorine;

each R ⁶ , R ⁷ , R ^{x is} independently selected from hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl, monocyclic aryl, alkenyl, and alkynyl; preferably each R ⁶ , R ⁷ , R ^{x is} independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl; more preferably, each R ⁶ , R ⁷ , R ^{x is} independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl; moreover, preferably each R ⁶ , R ⁷ , R ^{x is} independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from halo, cyano, C1-C8 alkyl, C3-C8 cyclyl, 3-8 membered heterocyclyl, aryl, heteroaryl, formyl, -NR ⁸ R ⁹ , -C(O)R ¹⁰ , carboxyl, alkenyl, alkynyl, -OR ¹⁰ , -OC(O)NR ⁸ R ⁹ , -C(O)OR ¹⁰ , -C(O)NR ⁸ R ⁹ , -NR ¹¹ C(O)R ¹⁰ , -NR ¹¹ C(O)NR ⁸ R ⁹ , -S(O)mR ¹⁰ , -NR ¹¹ S(O)mR ¹⁰ , -SR ¹⁰ , -S(O)mNR ⁸ R ⁹ and -NR ¹¹ S(O)mNR ⁸ R ⁹ ; preferably G1 is selected from halogen, C1-C6 alkyl, -OR ¹⁰ , -NR ⁸ R ⁹ ; more preferably G1 is selected from halogen, C1-C4 alkyl, -OR ¹⁰ , -NR ⁸ R ⁹ , wherein the alkyl is optionally substituted with one or more substituents selected from halogen, -OR ¹⁶ , -NR ¹³ R ¹⁴ ; if two G1s are attached to the same carbon atom or to two adjacent carbons, then the two G1s may form a 3-8 membered cyclyl together with the carbon atom(s) attached to them, preferably may form 3-6 -membered cycloalkyl, wherein the cycloalkyl formed is optionally substituted with one or more substituents selected from halo, OR ¹⁶ and -NR ¹³ R ¹⁴ ;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ is independently selected from the group consisting of hydrogen, C1-C8 alkyl, C1-C8 haloalkyl, heteroalkyl, C3-C8 cyclyl, 3-8-membered monocyclic heterocyclyl, monocyclic heteroaryl, monocyclic aryl, alkenyl and alkynyl, while R ⁸ and R ⁹ , R ¹³ and R ¹⁴ can form a 3-7-membered heterocyclyl;

and m is 1 or 2;

whereby the following compounds (1) - (7) are excluded:

2. The compound according to claim 1 and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts,

wherein

L ₁ is selected from -NR ⁶ C(O)-, -NR ⁶ CON(R ⁷ )-, -NR ⁶ S(O) _m - and -NR ⁶ S(O) _m N(R ⁷ )-, in which NR ⁶ is connected to a nitrogen-containing heteroaryl substituted with R ¹ , R ² , R ³ ;

L ₂ is selected from C1-C6 alkylene, C2-C6 alkenylene, C2-C6 alkynylene and C3-C6 cyclylene, wherein alkylene, alkenylene, alkynylene and cyclylene may be optionally substituted with one or more G1;

L ₃ is selected from a single bond and -O-;

each R ¹ , R ² , R ³ is independently selected from hydrogen, halogen, C1-C6 alkyl, C3-C6 cyclyl, 3-6 membered heterocyclyl, aryl, and heteroaryl, wherein alkyl, cyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or several substituents selected from halogen, cyano, C1-C6 alkyl, C3-C6 cyclyl and 3-6 membered heterocyclyl;

R ⁴ is selected from hydrogen, halogen, -NR ⁸ R ⁹ , -OR ¹⁰ ;

R ⁵ is selected from hydrogen, halogen, C1-C6 alkyl and C3-C6 cyclyl;

each R ⁶ , R ⁷ is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

G1 is selected from halogen, C1-C6 alkyl, -NR ⁸ R ⁹ , -OR ¹⁰ , wherein the alkyl is optionally substituted with one or more substituents selected from halogen, -NR ¹¹ R ¹² , -OR ¹⁶ ;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹⁶ is independently selected from hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

and m is 1 or 2;

whereby the following compounds (1) - (7) are excluded:

3. The compound according to claim 1 and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts,

wherein

L ₁ is selected from -NR ⁶ C(O)- and -NR ⁶ CON(R ⁷ )-, in which NR ⁶ is connected to a nitrogen-containing heteroaryl substituted with R ¹ , R ² , R ³ ;

L ₃ is selected from a single bond and -O-;

each R ¹ , R ² , R ³ is independently selected from hydrogen, halogen, C1-C4 alkyl, C4-C6 cyclyl, 4-6 membered heterocyclyl, with alkyl, cyclyl and heterocyclyl optionally substituted with one or more substituents selected from halogen;

R ⁴ is selected from hydrogen, halogen, -NR ⁸ R ⁹ , -OR ¹⁰ ;

R ⁵ is selected from hydrogen, halogen, C1-C6 alkyl and C3-C6 cyclyl;

R ⁶ , R ⁷ are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl;

whereby the following compounds (1) - (7) are excluded:

4. The compound according to claim 1 and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts,

wherein

L ₁ is selected from -NR ⁶ CON(R ⁷ )-, in which NR ⁶ is connected to a nitrogen-containing heteroaryl substituted with R ¹ , R ² , R ³ ;

L ₂ is selected from C1-C4 alkylene, C2-C4 alkenylene, C2-C4 alkynylene and C3-C4 cyclylene, wherein alkylene, alkenylene, alkynylene and cyclylene may be optionally substituted with one or more G1;

L ₃ is selected from a single bond and -O-;

each R ¹ , R ² , R ³ is independently selected from hydrogen, halogen and C1-C4 alkyl, with alkyl optionally substituted with one or more substituents selected from halogen;

R ⁴ is selected from hydrogen, halogen, -NR ⁸ R ⁹ , -OR ¹⁰ ;

R ⁵ is selected from hydrogen, halogen, C1-C6 alkyl and C3-C6 cyclyl;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹⁶ is independently selected from the group consisting of hydrogen, C1-C6 alkyl and C1-C6 haloalkyl;

whereby the following compounds (1) - (5) are excluded:

5. The compound according to claim 1 and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts,

wherein

L ₂ is selected from C1-C4 alkylene and C2-C4 alkenylene, while alkylene and alkenylene may be optionally substituted with one or more G1;

L ₃ is selected from a single bond and -O-;

R ⁴ is selected from hydrogen, halogen, -NR ⁸ R ⁹ , -OR ¹⁰ ;

R ⁵ is selected from hydrogen, halogen, C1-C4 alkyl and C3-C6 cyclyl;

each R ⁶ , R ⁷ is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;

G1 is selected from halogen, C1-C4 alkyl, -NR ⁸ R ⁹ , -OR ¹⁰ , wherein the alkyl is optionally substituted with one or more substituents selected from halogen, -NR ¹¹ R ¹² , -OR ¹⁶ ;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹⁶ is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl;

whereby the following compounds (1) - (5) are excluded:

6. The compound according to claim 1 and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts,

wherein

L ₂ is selected from C1-C4 alkylene, where the alkylene may be optionally substituted with one or more G1;

L ₃ is -O-;

R ⁴ is selected from hydrogen, halogen, -NR ⁸ R ⁹ , -OR ¹⁰ ;

R ⁵ is selected from hydrogen, halogen and C1-C4 alkyl;

each R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² and R ¹⁶ is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

whereby the following compounds (1) - (4) are excluded:

.

7. The compound according to claim 1 and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts,

wherein

L ₃ is -O-;

each R ¹ , R ² , R ³ is independently selected from hydrogen and halogen;

R ⁴ is selected from hydrogen and halogen;

R ⁵ is selected from hydrogen, halogen and C1-C4 alkyl and is located in the para position of L ₃ ;

each R ⁶ , R ⁷ is independently selected from hydrogen and C1-C4 alkyl;

G1 is selected from halogen, C1-C4 alkyl, wherein the alkyl is optionally substituted with one or more substituents selected from halogen, -NR ¹¹ R ¹² , -OR ¹⁶ ;

each R ¹¹ , R ¹² and R ¹⁶ is independently selected from hydrogen, C1-C4 alkyl and C1-C4 haloalkyl;

whereby the following compounds (1) - (4) are excluded:

.

8. The compound according to claim 1 and its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts, characterized in that the compounds are selected from:

.

9. Pharmaceutical composition containing a compound according to any one of paragraphs. 1-8 or its isomers, prodrugs, solvates, stable isotopic derivatives or pharmaceutically acceptable salts and pharmaceutically acceptable carriers, diluents and auxiliaries.

10. The use of a compound according to any one of paragraphs. 1-8 or its isomers, prodrugs, solvates, stable isotopic derivatives, or pharmaceutically acceptable salts, or the use of a pharmaceutical composition according to claim 9 in the preparation of a medicament for the treatment or prevention of TRK-mediated diseases such as cancer, especially hematological malignancies, lung cancer, cancer breast, ovarian cancer, prostate cancer, pancreatic cancer and glioma.