IP Library › Granted Patent US 11,286,264
Granted Patent B2
US 11,286,264 · App. 16/634,289 · Granted Mar 29, 2022

Macrocyclic compounds and uses thereof

Inventors: Jingrong Jean Cui (San Diego, CA); Evan W. Rogers (San Diego, CA); Jane Ung (San Diego, CA); Jeffrey Whitten (San Diego, CA); Dayong Zhai (San Diego, CA); Wei Deng (San Diego, CA); Xin Zhang (San Diego, CA); Zhongdong Huang (San Diego, CA); Jing Liu (San Diego, CA); Han Zhang (San Diego, CA)
Assignee: TURNING POINT THERAPEUTICS, INC.
C07D498/16A61P35/00C07K16/2863A61K45/06
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Quick Facts
Patent No.
US 11,286,264
App. No.
16/634,289
Granted
Mar 29, 2022
Kind
B2
Abstract

The present disclosure relates to certain macrocyclic compounds that inhibit SRC and MET, and/or CSF1R, pharmaceutical compositions containing such compounds, and methods of using such compounds to treat cancer.

Claims (34)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

X 1 and X 2 are independently —CR 6 R 7 —, S, S(O), S(O) 2 , O or N(R 8 );

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; or R 2 and R 4 taken together with the atoms to which they are attached optionally form 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 —NR 6 R 7 ;

each R 6 , R 7 and R 8 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 3 -C 6 cycloalkyl; wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, and C 3 -C 6 cycloalkyl is independently optionally substituted by deuterium, 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), or —C(O)N(C 1 -C 6 alkyl) 2 ;

R 9 is fluoro, chloro, bromo, —CN, —CF 3 , —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 10 is H, fluoro, chloro or bromo; and

n is 1 or 2.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are H.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 9 is CN.

4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 10 is fluoro.

5. The compound of claim 4 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N(R 8 ).

6. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 8 is C 1 C 6 alkyl, wherein each hydrogen atom 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), or —C(O)N(C 1 -C 6 alkyl) 2 .

7. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 8 is ethyl, propyl, iso-propyl, or cyclopropylmethyl.

8. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein X 2 is O.

9. The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein R 2 is 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 7 or —C(O)NR 7 R 8 ; 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, and R 3 is H.

10. The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 6 alkyl.

11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 2 is methyl.

12. The compound of claim 1 , selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one or more of a pharmaceutically acceptable diluent, carrier or excipient.

14. A method of treating cancer in a patient comprising,

a. administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the cancer is gastric cancer, colon cancer, renal cancer, liver cancer, lung cancer, glioblastoma, or head & neck cancer.

16. The method of claim 14 , further comprising

b. administering to the patient a therapeutically effective amount of at least one additional anti-cancer agent.

17. The method of claim 16 , wherein the at least one additional anti-cancer agent is an EGFR inhibitor, or a pharmaceutically acceptable salt thereof.

18. The method of claim 16 , wherein the additional anti-cancer agent is an antibody of EGFR.

19. The method of claim 18 , wherein the antibody of EGFR is cetuximab, necitumumab or panitumumab.

20. The method of claim 16 , wherein the additional anti-cancer agent is a small molecule inhibitor of EGFR.

21. The method of claim 20 , wherein the small molecule inhibitor of EGFR is afatinib, brigatinib, canertinib, dacomitinib, erlotinib, gefitinib, (2E)-N-[[4-[[(3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl]-4-(dimethylamino)-2-butenamide, lapatinib, osimertinib, naquotinib, nazartinib, neratinib, olmutinib, pelitinib, mavelertinib, rociletinib, vandetanib, or a pharmaceutically acceptable salt thereof.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 30, 2021
From: CUI, JINGRONG JEAN; ROGERS, EVAN W.; UNG, JANE; WHITTEN, JEFFREY; ZHAI, DAYONG; DENG, WEI; ZHANG, XIN; HUANG, ZHONGDONG; LIU, JING; ZHANG, HAN
To: TURNING POINT THERAPEUTICS, INC.
Reel/Frame 056724/0438 →
Continuity (3)
Provisional Application 62700990 · Jul 20, 2018
Provisional Application 62538193 · Jul 28, 2017
Related Publication 20200157119A1 · May 21, 2020
Cited By (1)
US 12,606,571