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US 2026/0265264 A1Published application
Spirocyclic dihydropyranopyrimidine kras inhibitors
AssigneeTreeline Biosciences, Inc.
InventorsShawn Cabral, Vincent Mascitti, Ludovic Jacky Gilbert Decultot, Jens-Martin Herold, Kevin D. Hesp, James Paul Lajiness, Alexander E. Seim, Florentina Tofoleanu, Andy Tsai
Life of this patent
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Abstract
Provided herein are compounds of Formula (IV-b), or pharmaceutically acceptable salts thereof, that inhibit a KRas protein (e.g., a dysregulated KRas protein (e.g., a mutated or amplified KRas protein)). This disclosure also provides compositions containing the compounds as provided herein, or pharmaceutically acceptable salts thereof, as well as methods of using and making the same.
Claims20
-76. (canceled)
A compound of Formula (II-a4), (II-a5), or (II-a8):
- or a pharmaceutically acceptable salt thereof, wherein:
- b4 is 0;
- each R10 is independently selected from the group consisting of:
- —Cl, —F, —CN, and C1-3 alkyl optionally substituted with 1-3 Rc;
- X1 is CH2;
- X2 is CH2;
- X3 is CHRL;
- RL is selected from the group consisting of C1-3 alkoxy, —F, CN, and C1-3 alkyl optionally substituted with 1-3 Rc;
- Y2 is —CH2—;
- R3 is
- optionally substituted with 1-2 substituents each independently selected from the group consisting of:
- —F, —C1-3 alkoxy, and —C1-3 haloalkoxy;
- each Rc is independently selected from the group consisting of:
- halo, cyano, —OH, —C1-6 alkoxy, —C1-6 haloalkoxy, —NRdRe, C(═O)C1-6 alkyl, C(═O)C1-6 haloalkyl, C(═O)OC1-6 alkyl, C(═O)OC1-6 haloalkyl, C(═O)OH, C(═O)N(Rf)2, S(O)0-2(C1-6 alkyl), S(O)0-2(C1-6 haloalkyl), and S(O)1-2N(Rf)2;
- each Rd and Re is independently selected from the group consisting of:
- H, C(═O)C1-6 alkyl, C(═O)C1-6 haloalkyl, C(═O)OC1-6 alkyl, C(═O)OC1-6 haloalkyl, C(═O)N(Rf)2, S(O)1-2(C1-6 alkyl), S(O)1-2(C1-6 haloalkyl), S(O)1-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh;
- each Rf is independently selected from the group consisting of:
- H and C1-6 alkyl optionally substituted with 1-3 Rh;
- and
- each Rh is independently selected from the group consisting of:
- halo, cyano, —OH, —C1-6 alkoxy, —C1-6 haloalkoxy, —NH2, —N(H)(C1-3 alkyl), and —N(C1-3 alkyl)2-.
18 more elements
A compound of Formula (II-a6) or (II-a7):
- or a pharmaceutically acceptable salt thereof, wherein:
- R7 is C1-3 alkyl substituted with —OH or C1-3 alkoxy;
- R7a is C1-3 alkyl substituted with —OH;
- R7b is selected from the group consisting of:
- C1-3 alkyl optionally substituted with 1-3 F, and
- C1-3 alkyl substituted with —OH or C1-3 alkoxy;
- b4 is 0;
- each R10 is independently selected from the group consisting of:
- —Cl, —F, —CN, and C1-3 alkyl optionally substituted with 1-3 Rc;
- X1 is CH2;
- X2 is CH2;
- X3 is CHRL;
- RL is selected from the group consisting of C1-3 alkoxy, —F, CN, and C1-3 alkyl optionally substituted with 1-3 Rc;
- Y2 is —CH2—;
- R3 is
- optionally substituted with 1-2 substituents each independently selected from the group consisting of:
- —F, —C1-3 alkoxy, and —C1-3 haloalkoxy;
- each Rc is independently selected from the group consisting of:
- halo, cyano, —OH, —C1-6 alkoxy, —C1-6 haloalkoxy, —NRdRe, C(═O)C1-6 alkyl, C(═O)C1-6 haloalkyl, C(═O)OC1-6 alkyl, C(═O)OC1-6 haloalkyl, C(═O)OH, C(═O)N(Rf)2, S(O)0-2(C1-6 alkyl), S(O)0-2(C1-6 haloalkyl), and S(O)1-2N(Rf)2;
- each Rd and Re is independently selected from the group consisting of:
- H, C(═O)C1-6 alkyl, C(═O)C1-6 haloalkyl, C(═O)OC1-6 alkyl, C(═O)OC1-6 haloalkyl, C(═O)N(Rf)2, S(O)1-2(C1-6 alkyl), S(O)1-2(C1-6 haloalkyl), S(O)1-2N(R)2, and C1-6 alkyl optionally substituted with 1-3 Rh;
- each Rf is independently selected from the group consisting of:
- H and C1-6 alkyl optionally substituted with 1-3 Rh;
- and
- each Rh is independently selected from the group consisting of:
- halo, cyano, —OH, —C1-6 alkoxy, —C1-6 haloalkoxy, —NH2, —N(H)(C1-3 alkyl), and —N(C1-3 alkyl)2-.
23 more elements
A compound of Formula (II-a3):
- or a pharmaceutically acceptable salt thereof, wherein:
- b4 is 0;
- each R10 is independently selected from the group consisting of:
- —Cl, —F, —CN, and C1-3 alkyl optionally substituted with 1-3 Rc;
- R7a is C(═O)N(Me)2;
- R7b is -halo or C1-3 alkyl;
- X1 is CH2;
- X2 and X3 are independently selected from the group consisting of:
- CH2, CHRL, C(RL)2, provided that 1-2 of X2 and X3 is independently CHRL or C(RL)2;
- RL is selected from the group consisting of C1-3 alkoxy, —F, CN, and C1-3 alkyl optionally substituted with 1-3 Rc;
- Y2 is —CH2—;
- R3 is
- optionally substituted with 1-2 substituents each independently selected from the group consisting of:
- —F, —C1-3 alkoxy, and —C1-3 haloalkoxy;
- each Rc is independently selected from the group consisting of:
- halo, cyano, —OH, —C1-6 alkoxy, —C1-6 haloalkoxy, —NRdRe, C(═O)C1-6 alkyl, C(═O)C1-6 haloalkyl, C(═O)OC1-6 alkyl, C(═O)OC1-6 haloalkyl, C(═O)OH, C(═O)N(Rf)2, S(O)0-2(C1-6 alkyl), S(O)0-2(C1-6 haloalkyl), and S(O)1-2N(Rf)2;
- each Rd and Re is independently selected from the group consisting of:
- H, C(═O)C1-6 alkyl, C(═O)C1-6 haloalkyl, C(═O)OC1-6 alkyl, C(═O)OC1-6 haloalkyl, C(═O)N(Rf)2, S(O)1-2(C1-6 alkyl), S(O)1-2(C1-6 haloalkyl), S(O)1-2N(Rf)2, and C1-6 alkyl optionally substituted with 1-3 Rh;
- each Rf is independently selected from the group consisting of:
- H and C1-6 alkyl optionally substituted with 1-3 Rh;
- and
- each Rh is independently selected from the group consisting of:
- halo, cyano, —OH, —C1-6 alkoxy, —C1-6 haloalkoxy, —NH2, —N(H)(C1-3 alkyl), and —N(C1-3 alkyl)2-.
20 more elements
Dependencies are inferred from the claim text.