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US 2026/0130902 A1Published application
HIPK4 Degraders as Non-Hormonal Male Contraceptives
AssigneesThe Board of Trustees of the Leland Stanford Junior University, Sanford Burnham Prebys Medical Discovery Institute
InventorsJames Kenneth Chen, Zaile Zhuang, Thomas D.Y. Chung, Patrick C. Kearney, Ian Pass, Andrey Bobkov, Shubhankar Dutta
Life of this patent
Estimating the term…
Abstract
Disclosed herein are compounds that abrogate the activity of HIPK4 by inhibiting the enzyme, inducing its degradation, or both. Also disclosed are methods for using the disclosed compounds as male contraceptives.
Claims20
A method for inhibiting HIPK4, comprising contacting the HIPK4 with a compound of the formula:
- or a pharmaceutically acceptable salt thereof,
- wherein
- R1 is independently selected from hydrogen, —X-LA-W, and C1-6 alkyl optionally substituted with one or more Ra, Rb, or both;
- R2 is independently selected from hydrogen, —X-LB-W, and C1-6 alkyl optionally substituted with one or more of the same or different Ra, Rb, or both;
- X is, for each occurrence, independently selected from a covalent bond,
- —C(O)—, —C(O)O—, —C(O)N(Rd)—, and —S(O)2—;
- LA is a linker;
- LB is a linker;
- W is a E3 ubiquitin ligase binding moiety;
- R3 and R4 are independently selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C6-16 arylalkyl, 2-6 membered heteroalkyl and 3-8 membered heterocyclylalkyl, each optionally substituted with one or more of the same or different Ra, Rb, or both, or R3 and R4 are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different which may optionally be substituted with one or more of the same or different Re groups;
- each Ra is independently selected from hydrogen, C1-8 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C6-16 arylalkyl, 2-6 membered heteroalkyl and 3-8 membered heterocyclylalkyl;
- Rb is independently selected from the group consisting of ═O, —ORa, halogen, C1-3haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, —SF5, halogen, —CF3, —CN, —NO2, —S(O)Rd, —S(O)2Rd, —S(O)2ORd,
- —N(H)S(O)2Rd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd,
- —OS(O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc,
- —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd,
- —OC(O)ORd,
- —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd,
- —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc,
- —[NRaC(O)]nNRcRc,
- —(CHRaCHRa—O)n—Ra, —[NHC(NH)]nNRcRc and —[NRaC(NRa)]nNRcRc;
- each Rc independently is hydrogen, Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 to 10-membered heterocyclylalkyl which may optionally include 1, 2 or 3 additional heteroatoms selected from O, N and S, and may optionally be substituted with one or more of the same or different Re groups;
- each Rd is independently hydrogen or C1-6 alkyl;
- each Re is independently Rd, ═O, —ORa, halogen, —C(O)Rd, and —S(O)2Rd;
- and
- each n is independently an integer from 0 to 3.
22 more elements
A method for inhibiting spermiogenesis, comprising administering an effective amount of a compound according to the formula:
- wherein
- R1 is independently selected from hydrogen, —X-LA-W, and C1-6 alkyl optionally substituted with one or more Ra, Rb, or both;
- R2 is independently selected from hydrogen, —X-LB-W, and C1-6 alkyl optionally substituted with one or more of the same or different Ra, Rb, or both;
- X is, for each occurrence, independently selected from a covalent bond,
- —C(O)—, —C(O)O—, —C(O)N(Rd)—, and —S(O)2—;
- LA is a linker;
- LB is a linker;
- W is a E3 ubiquitin ligase binding moiety;
- R3 and R4 are independently selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C6-16 arylalkyl, 2-6 membered heteroalkyl and 3-8 membered heterocyclylalkyl, each optionally substituted with one or more of the same or different Ra, Rb, or both, or R3 and R4 are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different which may optionally be substituted with one or more of the same or different Re groups;
- each Ra is independently selected from hydrogen, C1-8 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C6-16 arylalkyl, 2-6 membered heteroalkyl and 3-8 membered heterocyclylalkyl;
- Rb is independently selected from the group consisting of ═O, —ORa, halogen, C1-3haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, —SF5, halogen, —CF3, —CN, —NO2, —S(O)Rd, —S(O)2Rd, —S(O)2ORd,
- —N(H)S(O)2Rd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd,
- —OS(O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc,
- —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd,
- —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —(CHRaCH Ra—O)n—Ra, —[NHC(NH)]nNRcRc and —[NRaC(NRa)]nNRcRc;
- each Rc independently is hydrogen, Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 to 10-membered heterocyclylalkyl which may optionally include 1, 2 or 3 additional heteroatoms selected from O, N and S, and may optionally be substituted with one or more of the same or different Re groups;
- each Rd is independently hydrogen or C1-6 alkyl;
- each Re is independently Rd, ═O, —ORa, halogen, —C(O)Rd, and —S(O)2Rd;
- and
- each n is independently an integer from 0 to 3.
17 more elements
A compound of the formula:
- or a pharmaceutically acceptable salt thereof,
- wherein
- R1 is independently selected from hydrogen, —X-LA-W, and C1-6 alkyl optionally substituted with one or more Ra, Rb, or both;
- R2 is independently selected from hydrogen, —X-LB-W, and C1-6 alkyl optionally substituted with one or more of the same or different Ra, Rb, or both;
- provided that when R1 is hydrogen or C1-6 alkyl optionally substituted with one or more Ra, Rb, or both, R2 is —X-LB-W, and when R2 is hydrogen or C1-6 alkyl optionally substituted with one or more Ra, Rb, or both, R1 is —X-LA-W;
- X is, for each occurrence, independently selected from a covalent bond,
- —C(O)—, —C(O)O—, —C(O)N(Rd)—, and —S(O)2—;
- LA is a linker;
- LB is a linker;
- W is a E3 ubiquitin ligase binding moiety;
- R3 and R4 are independently selected from hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C6-16 arylalkyl, 2-6 membered heteroalkyl and 3-8 membered heterocyclylalkyl, each optionally substituted with one or more of the same or different Ra, Rb, or both, or R3 and R4 are taken together with the nitrogen atom to which they are bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different which may optionally be substituted with one or more of the same or different Re groups;
- each Ra is independently selected from hydrogen, C1-8 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C3-8 cycloalkyl, C6-10 aryl, C5-10 heteroaryl, C6-16 arylalkyl, 2-6 membered heteroalkyl and 3-8 membered heterocyclylalkyl;
- Rb is independently selected from the group consisting of ═O, —ORa, halogen, C1-3haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, —SF5, halogen, —CF3, —CN, —NO2, —S(O)Rd, —S(O)2Rd, —S(O)2ORd,
- —N(H)S(O)2Rd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd,
- —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —(CHRaCHRa—O)n—Ra, —[NHC(NH)]nNRcRc and —[NRaC(NRa)]nNRcRc;
- each Rc independently is hydrogen, Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 to 10-membered heterocyclylalkyl which may optionally include 1, 2 or 3 additional heteroatoms selected from O, N and S, and may optionally be substituted with one or more of the same or different Re groups;
- each Rd is independently hydrogen or C1-6 alkyl;
- each Re is independently Rd, ═O, —ORa, halogen, —C(O)Rd, and —S(O)2Rd;
- and
- each n is independently an integer from 0 to 3.
17 more elements
Dependencies are inferred from the claim text.