IP Library › Granted Patent US 11,008,337

Granted Patent B2

US 11,008,337 · App. 16/425,407 · Granted May 18, 2021

Chiral diaryl macrocycles as modulators of protein kinases

Inventors: Jingrong J. Cui (San Diego, CA); Yishan Li (San Diego, CA); Evan W. Rogers (San Diego, CA); Dayong Zhai (San Diego, CA); Wei Deng (San Diego, CA); Jane Ung (San Diego, CA)

Assignee: Turning Point Therapeutics, Inc.

C07D498/22 C07D498/14

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Quick Facts

Patent No.: US 11,008,337
App. No.: 16/425,407
Granted: May 18, 2021
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present disclosure relates to certain chiral diaryl macrocyclic derivatives, of the formula I: pharmaceutical compositions containing them, and methods of using them to treat cancer, pain, neurological diseases, autoimmune diseases, and inflammation.

Claims (99)

1. A method for modulating anaplastic lymphoma kinase activity or tropomysin receptor kinase A activity in a subject, comprising administering to the subject an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

n is 1 or 2;

M is CR 4 or N;

M 1 is CR 5 or N;

X 1 is —NR 9 —, —O—, —S—, —S(O)—, or —S(O) 2 -;

X 2 is —NR 9 —, —O—, —S—, —S(O)—, or —S(O) 2 -;

Z 1 is C, CR 10 , N, or NH;

Z 2 is C, CR 10 , N, or NH;

Z 3 is C, CR 10 , N, or NH;

Z 4 is C, CR 10 , N, or NH;

Z 5 is C, CR 10 , N, or NH;

Z 6 is C, CR 10 , N, or NH;

Z 7 is C, CR 10 , N, or NH;

R 1 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)NR 7 R 8 , C(O)OR 7 , C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl is optionally substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C(O)NH 2 , C(O)NHC 1 -C 6 alkyl, C(O)N(C 1 -C 6 alkyl) 2 , C(O)OH, C(O)OC 1 -C 6 alkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , NHC(O)C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, NHC(O)NH 2 , NHC(O)NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)NH 2 , N(C 1 -C 6 alkyl)C(O)NHC 1 -C 6 alkyl, NHC(O)N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , NHC(O)OC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, NHS(O)C 1 -C 6 alkyl, NHS(O) 2 C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, NHS(O)NH 2 , NHS(O) 2 NH 2 , N(C 1 -C 6 alkyl)S(O)NH 2 , N(C 1 -C 6 alkyl)S(O) 2 NH 2 , NHS(O)NHC 1 -C 6 alkyl, NHS(O) 2 NHC 1 -C 6 alkyl, NHS(O)N(C 1 -C 6 alkyl) 2 , NHS(O) 2 N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)S(O)NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O) 2 NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, P(C 1 -C 6 alkyl) 2 , P(O)(C 1 -C 6 alkyl) 2 , SC 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl, S(O)NHC 1 -C 6 alkyl, S(O)N(C 1 -C 6 alkyl) 2 , S( ) 2 C 1 -C 6 alkyl, S(O) 2 NHC 1 -C 6 alkyl, S(O) 2 N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, and 3- to 7-membered heterocycloalkyl;

R 2 and R 6 , taken together with the atoms to which they are attached, form a 5- to 7-membered heterocycloalkyl;

each R 3 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)NR 7 R 8 , C(O)OR 7 , C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, and C 6 -C 10 aryl is optionally and independently substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C(O)NH 2 , C(O)NHC 1 -C 6 alkyl, C(O)N(C 1 -C 6 alkyl) 2 , C(O)OH, C(O)OC 1 -C 6 alkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , NHC(O)C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, NHC(O)NH 2 , NHC(O)NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)NH 2 , N(C 1 -C 6 alkyl)C(O)NHC 1 -C 6 alkyl, NHC(O)N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , NHC(O)OC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, NHS(O)C 1 -C 6 alkyl, NHS(O) 2 C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, NHS(O)NH 2 , NHS(O) 2 NH 2 , N(C 1 -C 6 alkyl)S(O)NH 2 , N(C 1 -C 6 alkyl)S(O) 2 NH 2 , NHS(O)NHC 1 -C 6 alkyl, NHS(O) 2 NHC 1 -C 6 alkyl, NHS(O)N(C 1 -C 6 alkyl) 2 , NHS(O) 2 N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)S(O)NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O) 2 NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, P(C 1 -C 6 alkyl) 2 , P(O)(C 1 -C 6 alkyl) 2 , SC 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl, S(O)NHC 1 -C 6 alkyl, S(O)N(C 1 -C 6 alkyl) 2 , S(O) 2 C 1 -C 6 alkyl, S(O) 2 NHC 1 -C 6 alkyl, S(O) 2 N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, and 3- to 7-membered heterocycloalkyl;

R 4 is H, F, Cl, Br, CN, C 1 -C 6 alkyl, CF 3 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, or OC 1 -C 6 alkyl;

R 4 , is H, F, Cl, Br, CN, C 1 -C 6 alkyl, CF 3 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, or OC 1 -C 6 alkyl;

R 5 is H, F, Cl, Br, CN, C 1 -C 6 alkyl, CF 3 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, or OC 1 -C 6 alkyl;

each R 7 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 1 aryl, or heteroaryl;

each R 8 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 1 aryl, or heteroaryl;

each R 9 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or monocyclic or bicyclic heteroaryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, and monocyclic or bicyclic heteroaryl is optionally and independently substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and OR 7 ; and

each R 10 is independently H, deuterium, halogen, CN, C 1 -C 6 alkyl, CF 3 , NH 2 , NHC 1 -C 6 alkyl, NH(phenyl), NH(heteroaryl), OH, or OC 1 -C 6 alkyl;

with the provisos that:

(1) at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 is N or NH; and

(2) at least one of R 1 and R 3 is not H.

2. The method of claim 1 , wherein the subject has cancer, inflammation, pain, an autoimmune disease, or ta neurological disease.

3. The method of claim 1 , wherein X 2 is—O—.

4. The method of claim 3 , wherein X 1 is—NR 9 -.

5. The method of claim 4 , wherein R 9 is H.

6. The method of claim 1 , wherein:

Z 1 is N;

Z 2 is CH;

Z 3 is CH;

Z 4 is N;

Z 5 is C;

Z 6 is CH; and

Z 7 is N.

7. The method of claim 1 , wherein each R 3 is independently C 1 -C 6 alkyl, wherein each C 1 -C 6 alkyl is optionally and independently substituted.

8. The method of claim 1 , wherein each R 3 is independently H.

9. The method of claim 8 , wherein R 5 is H.

10. The method of claim 9 , wherein R 4 is F.

11. The method of claim 1 , wherein the compound has formula Ia:

or a pharmaceutically acceptable salt thereof,

wherein:

R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)NR 7 R 8 , C(O)OR 7 , C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl is optionally substituted.

12. The method of claim 1 , wherein the compound has formula II:

or a pharmaceutically acceptable salt thereof,

wherein:

M is CH or N; and

13. The method of claim 1 , wherein the compound has formula III:

or a pharmaceutically acceptable salt thereof,

wherein:

M is CH or N; and

14. The method of claim 1 , wherein the compound has formula XI, formula XII, or formula XIII:

or a pharmaceutically acceptable salt thereof,

wherein:

M is CH or N; and

15. The method of claim 14 , wherein M is CH.

16. The method of claim 15 , wherein R 5 is H.

17. The method of claim 16 , wherein X 1 is—NH—.

18. The method of claim 17 , wherein X 2 is—O—.

19. The method of claim 18 , wherein R 1 is C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted.

20. The method of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21. A method for modulating anaplastic lymphoma kinase activity or tropomysin receptor kinase A activity in a subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising at least one diluent, carrier, or excipient and a compound of formula I:

or a pharmaceutically acceptable salt thereof,

wherein:

n is 1 or 2;

M is CR 4 or N;

M 1 is CR 5 or N;

X 1 is —NR 9 —, —O—, —S—, —S(O)—, or —S(O) 2 -;

X 2 is —NR 9 —, —O—, —S—, —S(O)—, or —S(O) 2 -;

Z 1 is C, CR 10 , N, or NH;

Z 2 is C, CR 10 , N, or NH;

Z 3 is C, CR 10 , N, or NH;

Z 4 is C, CR 10 , N, or NH;

Z 5 is C, CR 10 , N, or NH;

Z 6 is C, CR 10 , N, or NH;

Z 7 is C, CR 10 , N, or NH;

R 1 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C(O)NR 7 R 8 , C(O)OR 7 , C 3 -C 6 cycloalkyl, or C 6 -C 1 aryl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 6 -C 10 aryl is optionally substituted by one or more substituents independently selected from the group consisting of deuterium, halogen, CN, C(O)NH 2 , C(O)NHC 1 -C 6 alkyl, C(O)N(C 1 -C 6 alkyl) 2 , C(O)OH, C(O)OC 1 -C 6 alkyl, NH 2 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , NHC(O)C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)C 1 -C 6 alkyl, NHC(O)NH 2 , NHC(O)NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)NH 2 , N(C 1 -C 6 alkyl)C(O)NHC 1 -C 6 alkyl, NHC(O)N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)C(O)N(C 1 -C 6 alkyl) 2 , NHC(O)OC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)C(O)OC 1 -C 6 alkyl, NHS(O)C 1 -C 6 alkyl, NHS(O) 2 C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O)C 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, NHS(O)NH 2 , NHS(O) 2 NH 2 , N(C 1 -C 6 alkyl)S(O)NH 2 , N(C 1 -C 6 alkyl)S(O) 2 NH 2 , NHS(O)NHC 1 -C 6 alkyl, NHS(O) 2 NHC 1 -C 6 alkyl, NHS(O)N(C 1 -C 6 alkyl) 2 , NHS(O) 2 N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)S(O)NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O) 2 NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl)S(O)N(C 1 -C 6 alkyl) 2 , N(C 1 -C 6 alkyl)S(O) 2 N(C 1 -C 6 alkyl) 2 , OH, OC 1 -C 6 alkyl, P(C 1 -C 6 alkyl) 2 , P(O)(C 1 -C 6 alkyl) 2 , SC 1 -C 6 alkyl, S(O)C 1 -C 6 alkyl, S(O)NHC 1 -C 6 alkyl, S(O)N(C 1 -C 6 alkyl) 2 , S(O) 2 C 1 -C 6 alkyl, S(O) 2 NHC 1 -C 6 alkyl, S(O) 2 N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, and 3- to 7-membered heterocycloalkyl;

R 2 and R 6 , taken together with the atoms to which they are attached, form a 5- to 7-membered heterocycloalkyl;

R 4 is H, F, Cl, Br, CN, C 1 -C 6 alkyl, CF 3 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, or OC 1 -C 6 alkyl;

R 4a is H, F, Cl, Br, CN, C 1 -C 6 alkyl, CF 3 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, or OC 1 -C 6 alkyl;

R 5 is H, F, Cl, Br, CN, C 1 -C 6 alkyl, CF 3 , NHC 1 -C 6 alkyl, N(C 1 -C 6 alkyl) 2 , OH, or OC 1 -C 6 alkyl;

each R 7 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 1 aryl, or heteroaryl;

each R 8 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 1 aryl, or heteroaryl;

each R 10 is independently H, deuterium, halogen, CN, C 1 -C 6 alkyl, CF 3 , NH 2 , NHC 1 -C 6 alkyl, NH(phenyl), NH(heteroaryl), OH, or OC 1 -C 6 alkyl;

with the provisos that:

(1) at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 is N or NH; and

(2) at least one of R 1 and R 3 is not H.

22. The method of claim 21 , wherein the subject has cancer, inflammation, pain, an autoimmune disease, or a neurological disease.

Assignments (1)

CHANGE OF NAME Recorded Aug 19, 2019

From: TP THERAPEUTICS, INC.

To: TURNING POINT THERAPEUTICS, INC.

Reel/Frame 050084/0756 →

Continuity (4)

Division 15740462

Provisional Application 62353728 · Jun 23, 2016

Provisional Application 62188043 · Jul 2, 2015

Related Publication 20190284209A1 · Sep 19, 2019