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US 12,606,572 B2Granted
Substituted heterocycles and uses thereof
AssigneeKumquat Biosciences Inc.
InventorsPingda Ren, Baogen Wu, Xiaoming Li, Xiaohui He, Liansheng Li
Life of this patent
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Abstract
The present disclosure provides compounds and pharmaceutically acceptable salts thereof, and methods of using the same. The compounds and methods have a range of utilities as therapeutics, diagnostics, and research tools. In particular, the subject compositions and methods are useful for reducing signaling output of oncogenic protein.
Claims20
A compound having the formula:
- or a pharmaceutically acceptable salt or solvate thereof, wherein:
- R10 and R11 are independently selected from hydrogen, halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), —OR12, —SR12, —N(R12)(R13), —C(O)OR12, —OC(O)N(R12)(R13), —N(R12)C(O)N(R12)(R13), —N(R12)C(O)OR12, —N(R12)S(O)2R12, —C(O)R12, —S(O)R12, —OC(O)R12, —C(O)N(R12)(R13), —C(O)C(O)N(R12)(R13), —N(R12)C(O)R12, —S(O)2R12, —S(O)(NR12)R12, —S(O)2N(R12)(R13), and —S(═O)(═NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;
- R19a is imidazol-1-yl optionally substituted with one or more R20;
- R20f is selected from hydrogen and R20;
- R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;
- R13 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;
- or R12 and R13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more R20;
- R20 is independently selected at each occurrence from halogen, oxo, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), —OR22, —SR22, —N(R22)(R23), ═NR22, ═C(R21)2, —C(O)OR22, —OC(O)N(R22)(R23), —N(R22)C(O)N(R22)(R23), —N(R22)C(O)OR22, —N(R22)S(O)2R22, —C(O)R22, —S(O)R22, —OC(O)R22, —C(O)N(R22)(R23), —C(O)C(O)N(R22)(R23), —N(R22)C(O)R22, —S(O)2R22, —S(O)(NR22)R22, —S(O)2N(R22)(R23), and —S(═O)(═NR22)N(R22)(R23);
- wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more substituents independently selected from halogen, oxo, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, —OR22, —SR22, —N(R22)(R23), ═NR22, ═C(R21)2, —C(O)OR22, —OC(O)N(R22)(R23), —N(R22)C(O)N(R22)(R23), —N(R22)C(O)OR22, —N(R22)S(O)2R22, —C(O)R22, —S(O)R22, —OC(O)R22, —C(O)N(R22)(R23), —C(O)C(O)N(R22)(R23), —N(R22)C(O)R22, —S(O)2R22, —S(O)(NR22)R22, —S(O)2N(R22)(R23), and —S(═O)(═NR22)N(R22)(R23);
- R21 is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle), or two R21 are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and —OH;
- R22 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle);
- and
- R23 is independently selected at each occurrence from hydrogen and C1-6 alkyl;
- or R22 and R23 attached to the same nitrogen atom form 3- to 10 membered heterocycle.
11 more elements
A method of treating cancer comprising a K-Ras G12S mutant protein in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound having the formula:
- or a pharmaceutically acceptable salt or solvate thereof, wherein:
- R10 and R11 are independently selected from hydrogen, halogen, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), —OR12, —SR12, —N(R12)(R13), —C(O)OR12, —OC(O)N(R12)(R13), —N(R12)C(O)N(R12)(R13), —N(R12)C(O)OR12, —N(R12)S(O)2R12, —C(O)R12, —S(O)R12, —OC(O)R12, —C(O)N(R12)(R13), —C(O)C(O)N(R12)(R13), —N(R12)C(O)R12, —S(O)2R12, —S(O)(NR12)R12, —S(O)2N(R12)(R13), and —S(═O)(═NR12)N(R12)(R13), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;
- R19a is imidazol-1-yl optionally substituted with one or more R20;
- R20f is selected from hydrogen and R20;
- R12 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle), wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle) are optionally substituted with one or more R20;
- R13 is independently selected at each occurrence from hydrogen, C1-6 alkyl, and C1-6 haloalkyl;
- or R12 and R13 attached to the same nitrogen atom form 3- to 10-membered heterocycle optionally substituted with one or more R20;
- R20 is independently selected at each occurrence from halogen, oxo, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle), —OR22, —SR22, —N(R22)(R23), ═NR22, ═C(R21)2, —C(O)OR22, —OC(O)N(R22)(R23), —N(R22)C(O)N(R22)(R23), —N(R22)C(O)OR22, —N(R22)S(O)2R22, —C(O)R22, —S(O)R22, —OC(O)R22, —C(O)N(R22)(R23), —C(O)C(O)N(R22)(R23), —N(R22)C(O)R22, —S(O)2R22, —S(O)(NR22)R22, —S(O)2N(R22)(R23), and —S(═O)(═NR22)N(R22)(R23);
- wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 2- to 6-membered heteroalkyl, 3- to 6-membered heteroalkenyl, 3- to 6-membered heteroalkynyl, —C0-6 alkyl-(C3-12 carbocycle), -(2- to 6-membered heteroalkyl)-(C3-12 carbocycle), —C0-6 alkyl-(3- to 12-membered heterocycle), and -(2- to 6-membered heteroalkyl)-(3- to 12-membered heterocycle) are optionally substituted with one or more substituents independently selected from halogen, oxo, —CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, —OR22, —SR22, —N(R22)(R23), ═NR22, ═C(R21)2, —C(O)OR22, —OC(O)N(R22)(R23), —N(R22)C(O)N(R22)(R23), —N(R22)C(O)OR22, —N(R22)S(O)2R22, —C(O)R22, —S(O)R22, —OC(O)R22, —C(O)N(R22)(R23), —C(O)C(O)N(R22)(R23), —N(R22)C(O)R22, —S(O)2R22, —S(O)(NR22)R22, —S(O)2N(R22)(R23), and —S(═O)(═NR22)N(R22)(R23);
- R21 is independently selected at each occurrence from hydrogen, halogen, C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle), or two R21 are taken together with the carbon atom to which they are attached to form C3-12 carbocycle or 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, C1-3 alkyl, C1-3 haloalkyl, and —OH;
- R22 is independently selected at each occurrence from hydrogen, C1-6 alkyl, C1-6 haloalkyl, —C0-6 alkyl-(C3-12 carbocycle), and —C0-6 alkyl-(3- to 12-membered heterocycle);
- and
- R23 is independently selected at each occurrence from hydrogen and C1-6 alkyl;
- or R22 and R23 attached to the same nitrogen atom form 3- to 10 membered heterocycle.
11 more elements
Dependencies are inferred from the claim text.