IP Library › Granted Patent US 10,689,400
Granted Patent B2
US 10,689,400 · App. 16/320,589 · Granted Jun 23, 2020

Macrocycle kinase inhibitors

Inventors: Jingrong Jean Cui (San Diego, CA); Yishan Li (San Diego, CA); Evan W. Rogers (San Diego, CA); Dayong Zhai (San Diego, CA); Jane Ung (San Diego, CA)
Assignee: Turning Point Therapeutics, Inc.
C07D498/18A61K45/06
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Quick Facts
Patent No.
US 10,689,400
App. No.
16/320,589
Granted
Jun 23, 2020
Kind
B2
Abstract

The present disclosure relates to certain macrocyclic kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same to treat disease.

Claims (31)

1. A method of treating cancer, pain, neurological diseases, autoimmune diseases, or inflammation comprising administering to a subject in need of such treatment an effective amount of at least one compound of the formula Ic

or a pharmaceutically acceptable salt thereof,

wherein

R 1 is H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, —C(O)OR 8 or —C(O)NR 8 R 9 ; wherein each hydrogen atom in 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 independently optionally substituted by deuterium, halogen, —OH, —CN, —OC 1 -C 6 alkyl, —NH 2 , —NH(C 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)NH(C 1 -C 6 alkyl), —NHS(O) 2 NH(C 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)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH(C 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 , —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —P(C 1 -C 6 alkyl) 2 , —P(O)(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl;

each R 2 and R 3 is independently H, deuterium, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 10 aryl, —C(O)OR 8 or —C(O)NR 8 R 9 ; wherein each hydrogen atom in 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 independently optionally substituted by deuterium, halogen, —OH, —CN, —OC 1 -C 6 alkyl, —NH 2 , —NH(C 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)NH(C 1 -C 6 alkyl), —NHS(O) 2 NH(C 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)NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)S(O) 2 NH(C 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 , —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , —SC 1 -C 6 alkyl, —S(O)C 1 -C 6 alkyl, —S(O) 2 C 1 -C 6 alkyl, —S(O)NH(C 1 -C 6 alkyl), —S(O) 2 NH(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —P(C 1 -C 6 alkyl) 2 , —P(O)(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or 3- to 7-membered heterocycloalkyl; or R 2 and R 3 taken together with the carbon atoms to which they are attached optionally form a C 5 -C 7 cycloalkyl or a 5- to 7-membered heterocycloalkyl;

R 4 is H, C 1 -C 6 alkyl or 3- to 7-membered heterocycloalkyl, wherein each hydrogen atom in C 1 -C 6 alkyl or 3- to 7-membered heterocycloalkyl is independently optionally substituted by halogen, —OH, —CN, —OC 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl), —C(O)N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, or monocyclic 5- to 7-membered heterocycloalkyl;

R 5 is selected from the group consisting of fluoro, chloro, bromo, C 1 -C 6 alkyl, —OH, —CN, —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, 3- to 7-membered heterocycloalkyl, —O—(C 3 -C 6 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), 5- to 7-membered heteroaryl, C 6 -C 10 aryl, and CF 3 ; wherein each hydrogen atom in C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , C 3 -C 6 cycloalkyl, 3- to 7-membered -heterocycloalkyl, —O—(C 3 -C 6 cycloalkyl), —O-(3- to 7-membered heterocycloalkyl), 5- to 7-membered heteroaryl and C 6 -C 10 aryl is independently optionally substituted by fluoro, chloro, bromo, —OH, —CN, —OC 1 -C 6 alkyl, —NH 2 , NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , C 3 -C 7 cycloalkyl, 3- to 7-membered heterocycloalkyl, C 6 -C 10 aryl, 5- to 7-membered heteroaryl, —CO 2 H, —C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl) and —C(O)N(C 1 -C 6 alkyl) 2 ;

R 6 is selected from the group consisting of H, fluoro, chloro, bromo, C 1 -C 6 alkyl —OH, —CN, —OC 1 -C 6 alkyl, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , 5- to 7-membered heteroaryl, C 6 -C 10 aryl, and -CF 3 ; wherein each hydrogen atom in C 1 -C 6 alkyl, 5- to 7-membered heteroaryl and C 6 -C 10 aryl is independently optionally substituted by fluoro, chloro, bromo, —OH, —CN, —OC 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, C(O)OC 1 -C 6 alkyl, —C(O)NH 2 , —C(O)NH(C 1 -C 6 alkyl) and —C(O)N(C 1 -C 6 alkyl) 2 ;

R 7 is H;

each R 8 and 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 heteroaryl;

R 10 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 mono- or bicyclic heteroaryl: wherein each hydrogen atom in 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 mono- or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or —OR 8 ; and

n is 1 or 2;

and wherein the disease is mediated by Bruton's tyrosine kinase (BTK).

2. The method of claim 1 , wherein R 6 is fluoro.

3. The method of claim 2 , wherein R 5 is fluoro, chloro, bromo, —OH, methoxy, ethoxy, iso-propoxy, or n-propoxy.

4. The method of claim 1 , wherein R 3 is H.

5. The method of claim 1 , wherein R 4 is H.

6. The method of claim 1 , wherein R 1 and R 2 are each independently H or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted with deuterium, halogen, or —OH.

7. The method of claim 1 , wherein R 10 is H.

8. The method of claim 2 , wherein R 5 is selected from the group consisting of fluoro, chloro, bromo, —OH, —CN, —CF 3 , C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, and 5- to 7-membered heteroaryl.

9. The method of claim 8 , wherein R 3 is H.

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

11. The method of claim 10 , wherein R 1 and R 2 are each independently H or C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl is independently optionally substituted with deuterium, halogen, or —OH.

12. The method of claim 11 , wherein R 10 is H.

13. A method of treating cancer, pain, neurological diseases, autoimmune diseases, or inflammation comprising administering to a subject in need of such treatment an effective amount of at least one compound selected from the group consisting of

14. The method of claim 1 , wherein the disease is cancer.

15. The method of claim 14 , wherein the cancer is mediated by a genetically altered BTK.

16. The method of claim 15 , wherein the genetically altered BTK comprises at least one resistance mutation.

17. The method of claim 16 , wherein the at least one resistance mutation is C481S.

18. The method of claim 14 , wherein the cancer is selected from the group consisting of NSCLC, triple negative breast cancer, leukemia, myeloproliferative neoplasms, chronic lymphocytic leukemia, mantle cell leukemia and pancreas adenocarcinoma lung cancer, colon cancer, breast cancer, prostate cancer, hepatocellular carcinoma, renal cell carcinoma, gastric and esophago-gastric cancers, glioblastoma, head and neck cancers, inflammatory myofibroblastic tumors, and anaplastic large cell lymphoma.

19. The method of claim 18 , wherein the cancer is NSCLC.

Assignments (3)
CORRECTIVE ASSIGNMENT TO CORRECT THE TYPOGRAPHICAL ERROR IN THE NAME OF INVENTOR FROM "ZHAI, ZHAI" TO ZHAI, DAYONG" PREVIOUSLY RECORDED AT REEL: 052567 FRAME: 0656. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded May 15, 2020
From: CUI, JINGRONG J.; LI, YISHAN; ROGERS, EVAN W.; ZHAI, DAYONG; UNG, JANE
To: TP THERAPEUTICS, INC.
Reel/Frame 052678/0680 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 5, 2020
From: CUI, JINGRONG J.; LI, YISHAN; ROGERS, EVAN W.; ZHAI, ZHAI; UNG, JANE
To: TP THERAPEUTICS, INC.
Reel/Frame 052567/0656 →
CHANGE OF NAME Recorded Aug 19, 2019
From: TP THERAPEUTICS, INC.
To: TURNING POINT THERAPEUTICS, INC.
Reel/Frame 050084/0756 →
Continuity (2)
Provisional Application 62367886 · Jul 28, 2016
Related Publication 20190169208A1 · Jun 6, 2019
Cited By (3)
US 12,351,572 US 12,606,571 US 12,679,850