IP Library › Granted Patent US 10,316,044

Granted Patent B2

US 10,316,044 · App. 15/740,462 · Granted Jun 11, 2019

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: TP Therapeutics, Inc.

C07D498/22 C07D498/14

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Quick Facts

Patent No.: US 10,316,044
App. No.: 15/740,462
Granted: Jun 11, 2019
Kind: B2

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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 (73)

1. A compound of the formula I

wherein

M is CR 4a or N;

M 1 is CR 5 or N;

X 1 and X 2 are independently S, S(O), S(O) 2 , O or N(R 9 );

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 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;

each 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 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;

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

R 4 , R 4a and R 5 are each independently 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 or —CF 3 ;

each R 7 and 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 10 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 or monocyclic 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 or monocyclic or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or —OR 7 ;

Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 are each independently N, NH, C, or C(R 10 ), wherein each R 10 , when present, is independently H, deuterium, halogen, C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —NH(phenyl), —NH(heteroaryl), —CN, or —CF 3 , and

n is 1 or 2;

provided that at least one of Z 1 , Z 2 , Z 3 , Z 4 , z 5 , z 6 , and Z 7 is N or NH; and provided that at least one R 1 , R 2 or R 3 is not H;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M 1 is CH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is CH, and M 1 is CH.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is C 1 -C 6 alkyl; wherein each hydrogen atom in C 1 -C 6 alkyl 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.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is fluoro.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is H.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N(R 9 ).

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 2 is O.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 , Z 4 and Z 7 are independently N, Z 5 is C, and Z 2 , Z 3 , and Z 6 are independently CH.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the formula Ia

wherein

M is CR 4a or N;

X 1 and X 2 are independently S, S(O), S(O) 2 , O or N(R 9 );

R 1 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;

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

R 4 , R 4a and R 5 are each independently 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 or —CF 3 ;

each R 7 and 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 10 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 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 monocyclic or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or —OR 7 ; and

Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 are each independently N, NH, C, or C(R 10 ), wherein each R 10 is independently H, deuterium, halogen, C 1 -C 6 alkyl, —OC 1 -C 6 alkyl, —OH, —NH 2 , —NH(C 1 -C 6 alkyl), —NH(phenyl), —NH(heteroaryl), —CN, or —CF 3 ,

provided that at least one of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , and Z 7 is N or NH.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the formula II

wherein

M is CH or N;

X 1 and X 2 are independently S, S(O), S(O) 2 , O or N(R 9 );

R 1 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;

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

R 4 and R 5 are each independently 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 or —CF 3 ;

each R 7 and 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 10 aryl, or heteroaryl; and

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has the formula III

wherein

M is CH or N;

X 1 and X 2 are independently S, S(O), S(O) 2 , O or N(R 9 );

R 1 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;

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

R 4 and R 5 are each independently 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 or —CF 3 ;

each R 7 and 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 10 aryl, or heteroaryl; and

15. The compound of claim 1 , wherein the compound has the formula XI, formula XII or formula XIII

wherein

M is CH or N;

X 1 and X 2 are independently S, S(O), S(O) 2 , O or N(R 9 );

R 1 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;

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

R 4 and R 5 are each independently 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 or —CF 3 ;

each R 7 and 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 10 aryl, or heteroaryl; and

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 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 monocyclic or bicyclic heteroaryl is independently optionally substituted by deuterium, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl or —OR 7 ;

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein M is CH.

17. The compound of claim 16 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H.

18. The compound of claim 17 , or a pharmaceutically acceptable salt thereof, wherein X 1 is NH.

19. The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein X 2 is O.

20. The compound of claim 19 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 1 -C 6 alkyl, wherein each hydrogen atom in C 1 -C 6 alkyl 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.

21. The compound of claim 1 , wherein the compound is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

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

Assignments (1)

CHANGE OF NAME Recorded Aug 19, 2019

From: TP THERAPEUTICS, INC.

To: TURNING POINT THERAPEUTICS, INC.

Reel/Frame 050084/0756 →

Continuity (3)

Provisional Application 62188043 · Jul 2, 2015

Provisional Application 62353728 · Jun 23, 2016

Related Publication 20180186813A1 · Jul 5, 2018

Cited By (7)

US 50,634 US 12,187,739 US 12,310,968 US 12,351,572 US 12,404,281 US 12,606,571 US 12,679,850