IP Library › Granted Patent US 12,594,275
Granted Patent B2
US 12,594,275 · App. 17/427,039 · Granted Apr 7, 2026

Immunophilin binding agents and uses thereof

Inventors: Kevan M. Shokat (San Francisco, CA); Ziyang Zhang (San Francisco, CA); William A. Weiss (San Francisco, CA); QiWen Fan (San Francisco, CA)
Assignee: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
A61K31/506A61K31/444A61K31/496A61K31/517
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Quick Facts
Patent No.
US 12,594,275
App. No.
17/427,039
Granted
Apr 7, 2026
Kind
B2
Abstract

Described herein, inter alia, are immunophilin binding compounds and methods of heating CNS diseases, including co-administering outside the CNS of a subject an anti-CNS disease drug and a compound described herein.

Claims (65)

1 . A method of treating a CNS disease in a subject in need of such treatment, comprising co-administering outside the CNS of said subject an anti-CNS disease drug and a compound having the formula:

A B -L B1 -R B1 , or a pharmaceutically acceptable salt thereof,

wherein

A B is an immunophilin-binding moiety;

L B1 -R B1 is a polar moiety;

L B1 is a bond, a covalent linker, or a bioconjugate linker;

R B1 is hydrogen, halogen, —CXB 3 1 , —CHXB 2 1 , —CH 2 X B1 , —OCXB 3 1 , —OCH 2 X B1 , —OCHXB 2 1 , —CN, —SO nB1 R B1D , —SO vB1 NR B1A R B1B , —NHC(O)NR B1A R B1B , —N(O) m B1 , —NR B1A R B1B , —C(O)R B1C , —C(O)OR B1C , —C(O)NR B1A R B1B , —OR B1D , —NR B1A SO 2 R B1D , —NR B1A C(O)R B1C , —NR B1A C(O)OR B1C , —NR B1A OR B1C , —NR B1A C(NR B1C ) R B1D , —NR B1A C(NR B1C )NR B1A R B1B , —N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R B1A , R B1B , R B1C , and R B1D are independently hydrogen, halogen, —CCl 3 , —CBr 3 , —CF 3 , —Cl 3 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHC(NH)H, —NHC(NH)NH 2 , —NHOH, —OCCl 3 , —OCBr 3 , —OCF 3 , —OCI 3 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 F, —OCH 2 I, —OCHCl 2 , —OCHBr 2 , —OCHF 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R B1A and R B1B substituents bonded to the same nitrogen atom may be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

nB1 is an integer from 0 to 4;

mB1 and vB1 are independently 1 or 2;

X B1 is independently —F, —Cl, —Br, or —I;

when L B1 is a bond, R B1 is not H;

wherein the anti-CNS disease drug has the formula:

A-L 1 -R 1 ;

wherein

A is an immunophilin-binding moiety;

L 1 is a bond or a covalent linker; and

R 1 is a monovalent kinase inhibitor, a monovalent pseudokinase inhibitor, a monovalent GTPase inhibitor, a monovalent histone-modifying enzyme inhibitor, a monovalent anti-cancer agent, a monovalent anti-neurodegenerative disease agent, or a monovalent anti-viral agent;

wherein the anti-CNS disease drug is capable of entering the central nervous system and the compound is incapable of entering the central nervous system following co-administration outside of the central nervous system of the subject.

2 . The method of claim 1 , wherein the immunophilin-binding moiety of the compound is a cyclophilin-binding moiety or an FKBP-binding moiety.

3 . The method of claim 1 , wherein L B1 is L B2 -L B3 -L B4 , L B2 is a bond, —S(O) 2 —, —N(R B2 )—, —O—, —S—, —C(O)—, —C(O)N(R B2 )—, —N(R B2 )C(O)—, —N(R B2 )C(O)NH—, —NHC(O)N(R B2 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L B3 is a bond, —S(O) 2 —, —N(R B3 )—, —O—, —S—, —C(O)—, —C(O)N(R B3 )—, —N(R B3 )C(O)—, —N(R B3 )C(O)NH—, —NHC(O)N(R B3 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L B4 is a bond, —S(O) 2 —, —N(R B4 )—, —O—, —S—, —C(O)—, —C(O)N(R B4 )—, —N(R B4 )C(O)—, —N(R B4 )C(O)NH—, —NHC(O)N(R B4 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

R B2 , R B3 , and R B4 are independently hydrogen, halogen, —CCl 3 , —CBr 3 , —CF 3 , -Cl 3 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHC(NH)H, —NHC(NH)NH 2 , —NHOH, —OCCl 3 , —OCBr 3 , —OCF 3 , —OCI 3 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 F, —OCH 2 I, —OCHCl 2 , —OCHBr 2 , —OCHF 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

4 . The method of claim 1 , wherein R B1 is halogen, —NR B1A R B1B , —N 3 , —SR B1D ,

R B10 is hydrogen, halogen, —CX 3 B10 , —CHX 2 10 , —CH 2 X B10 , —OCX 3 B10 , —OCH 2 X B10 , —OCHX 2 10 , —CN, —SO nB10 R B10D , —SO vB10 NR B10A R B10B , —NHC(O)NR B10A R B10B , —N(O) m B10 , —NR B10A R B10B , —C(O)R B10C , —C(O)OR B10C , —C(O)NR B10A R B10B , —OR B10D , —NR B10A SO 2 R B10D , —NR B10A C(O)R B10C , —NR B10A C(O)OR B10C , —NR B10A OR B10C , —NR B10A C(NR B10C ) R B10D , —NR B10A C(NR B10C )NR B10A R B10B , —N 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

nB10 is an integer from 0 to 4;

mB10 and v10 are independently 1 or 2; and

X B10 is independently —F, —Cl, —Br, or —I.

5 . The method of claim 1 , wherein the immunophilin-binding moiety of the compound is

or a stereoisomeric form thereof.

6 . The method of claim 1 , wherein the immunophilin-binding moiety of the compound is

or a stereoisomeric form thereof.

7 . The method of claim 1 , wherein R B1 is —SO nB1 R B1D , —SO vB1 NR B1A R B1B , or —NR B1A SO 2 R B1D .

8 . The method of claim 1 , wherein R B1 is substituted or unsubstituted heterocycloalkyl.

9 . The method of claim 1 , wherein R 1 is

10 . The method of claim 1 , wherein the immunophilin-binding moiety of the anti-CNS disease drug is a cyclophilin-binding moiety or an FKBP-binding moiety.

11 . The method of claim 1 , wherein L 1 is L 2 -L 3 -L 4 -L 3 -L 6 ;

L 2 is connected directly to A;

L 2 is-S(O) 2 —, —N(R 2 )—, —O—, —S—, —C(O)—, —C(O)N(R 2 )—, —N(R 2 )C(O)—, —N(R 2 )C(O)NH—, —NHC(O)N(R 2 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L 3 is a bond, —S(O) 2 —, —N(R 3 )—, —O—, —S—, —C(O)—, —C(O)N(R 3 )—, —N(R 3 )C(O)—, —N(R 3 )C(O)NH—, —NHC(O)N(R 3 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L 4 is a bond, —S(O) 2 —, —N(R 4 )—, —O—, —S—, —C(O)—, —C(O)N(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )C(O)NH—, —NHC(O)N(R 4 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L 5 is a bond, —S(O) 2 —, —N(R 5 )—, —O—, —S—, —C(O)—, —C(O)N(R 5 )—, —N(R 5 )C(O)—, —N(R 5 )C(O)NH—, —NHC(O)N(R 5 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;

L 6 is a bond, —S(O) 2 —, —N(R 6 )—, —O—, —S—, —C(O)—, —C(O)N(R 6 )—, —N(R 6 )C(O)—, —N(R 6 )C(O)NH—, —NHC(O)N(R 6 )—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene; and

R 2 , R 3 , R 4 , R 5 , and R 6 are independently hydrogen, halogen, —CCl 3 , —CBr 3 , —CF 3 , —CI 3 , —CH 2 Cl, —CH 2 Br, —CH 2 F, —CH 2 I, —CHCl 2 , —CHBr 2 , —CHF 2 , —CHI 2 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHSO 2 H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl 3 , —OCBr 3 , —OCF 3 , —OCI 3 , —OCH 2 Cl, —OCH 2 Br, —OCH 2 F, —OCH 2 I, —OCHCl 2 , —OCHBr 2 , —OCHF 2 , —OCHI 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

12 . The method of claim 11 , wherein L 2 is a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;

L 3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;

L 4 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

L 5 is a bond; and

L 6 is a bond.

13 . The method of claim 11 , wherein L 2 is an unsubstituted C 3 -C 7 alkylene, an oxo-substituted C 3 -C 7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene;

L 3 is a bond, an unsubstituted C 3 -C 7 alkylene, an oxo-substituted C 3 -C 7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, an oxo-substituted 3 to 17 membered heteroalkylene, or an unsubstituted 5 to 6 membered heterocycloalkylene, and

L 4 is a bond, an unsubstituted C 3 -C 7 alkylene, an oxo-substituted C 3 -C 7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene;

L 5 is a bond; and

L 6 is a bond.

14 . The method of claim 1 , wherein L 1 is a bond, an unsubstituted C 3 -C 7 alkylene, an oxo-substituted C 3 -C 7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene.

15 . The method of claim 1 , wherein R 1 is a monovalent kinase inhibitor, a monovalent KRAS inhibitor, a monovalent MAP4K inhibitor, or a monovalent MAP3K inhibitor;

wherein the monovalent kinase inhibitor is a monovalent Src kinase inhibitor, a monovalent Raf inhibitor, a monovalent VEGFR inhibitor, a monovalent PDGFR inhibitor, a monovalent c-Kit inhibitor, a monovalent EGFR inhibitor, or a monovalent LRRK2 inhibitor.

16 . The method of claim 1 , wherein the immunophilin-binding moiety of the anti-CNS disease drug is

or a stereoisomeric form thereof.

17 . The method of claim 1 , wherein the immunophilin-binding moiety of the anti-CNS disease drug is

or a stereoisomeric form thereof.

18 . The method of claim 1 , wherein the CNS disease is cancer, a neurodegenerative disease, epilepsy, Tuberous Sclerosis (TSC), or a disease associated with aberrant enzyme activity.

19 . The method of claim 18 , wherein the CNS disease is epilepsy or TSC.

20 . The method of claim 18 , wherein the CNS disease is a neurodegenerative disease.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 12, 2025
From: SHOKAT, KEVAN M.; ZHANG, ZIYANG; WEISS, WILLIAM A.; FAN, QIWEN
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 070491/0858 →
Continuity (2)
Provisional Application 62802668 · Feb 7, 2019
Related Publication 20230063768A1 · Mar 2, 2023
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