# US 12,594,275 B2 · Immunophilin binding agents and uses thereof

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- Number: US 12,594,275 B2
- Document ID: US12594275B2
- Status: Granted
- Kind: B2
- Application number: 17/427,039
- Filed: 2020-02-06
- Published: 2023-03-02
- Granted: 2026-04-07
- Earliest claimed: 2019-02-07
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Kevan M. Shokat; Ziyang Zhang; William A. Weiss; QiWen Fan
- Web page: https://patentgrep.com/patent/US12594275B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 25/00: Drugs for disorders of the nervous system
- C07D 498/18: Bridged systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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

### Claim 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:
AB-LB1-RB1, or a pharmaceutically acceptable salt thereof,
wherein
AB is an immunophilin-binding moiety;
LB1-RB1 is a polar moiety;
LB1 is a bond, a covalent linker, or a bioconjugate linker;
RB1 is hydrogen, halogen, —CXB31, —CHXB21, —CH2XB1, —OCXB31, —OCH2XB1, —OCHXB21, —CN, —SOnB1RB1D, —SOvB1NRB1ARB1B, —NHC(O)NRB1ARB1B, —N(O)mB1, —NRB1ARB1B, —C(O)RB1C, —C(O)ORB1C, —C(O)NRB1ARB1B, —ORB1D, —NRB1ASO2RB1D, —NRB1AC(O)RB1C, —NRB1AC(O)ORB1C, —NRB1AORB1C, —NRB1AC(NRB1C) RB1D, —NRB1AC(NRB1C)NRB1ARB1B, —N3, 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;
RB1A, RB1B, RB1C, and RB1D are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —Cl3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHC(NH)H, —NHC(NH)NH2, —NHOH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCH2I, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, 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 RB1A and RB1B 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;
XB1 is independently —F, —Cl, —Br, or —I;
when LB1 is a bond, RB1 is not H;
wherein the anti-CNS disease drug has the formula:
A-L1-R1;
wherein
A is an immunophilin-binding moiety;
L1 is a bond or a covalent linker; and
R1 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The method of claim 1, wherein LB1 is LB2-LB3-LB4, LB2 is a bond, —S(O)2—, —N(RB2)—, —O—, —S—, —C(O)—, —C(O)N(RB2)—, —N(RB2)C(O)—, —N(RB2)C(O)NH—, —NHC(O)N(RB2)—, —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;
LB3 is a bond, —S(O)2—, —N(RB3)—, —O—, —S—, —C(O)—, —C(O)N(RB3)—, —N(RB3)C(O)—, —N(RB3)C(O)NH—, —NHC(O)N(RB3)—, —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;
LB4 is a bond, —S(O)2—, —N(RB4)—, —O—, —S—, —C(O)—, —C(O)N(RB4)—, —N(RB4)C(O)—, —N(RB4)C(O)NH—, —NHC(O)N(RB4)—, —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
RB2, RB3, and RB4 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, -Cl3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHC(NH)H, —NHC(NH)NH2, —NHOH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCH2I, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, 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.

### Claim 4 (depends on 1)

The method of claim 1, wherein RB1 is halogen, —NRB1ARB1B, —N3, —SRB1D,
RB10 is hydrogen, halogen, —CX3B10, —CHX210, —CH2XB10, —OCX3B10, —OCH2XB10, —OCHX210, —CN, —SOnB10RB10D, —SOvB10NRB10ARB10B, —NHC(O)NRB10ARB10B, —N(O)mB10, —NRB10ARB10B, —C(O)RB10C, —C(O)ORB10C, —C(O)NRB10ARB10B, —ORB10D, —NRB10ASO2RB10D, —NRB10AC(O)RB10C, —NRB10AC(O)ORB10C, —NRB10AORB10C, —NRB10AC(NRB10C) RB10D, —NRB10AC(NRB10C)NRB10ARB10B, —N3, 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
XB10 is independently —F, —Cl, —Br, or —I.

### Claim 5 (depends on 1)

The method of claim 1, wherein the immunophilin-binding moiety of the compound is
or a stereoisomeric form thereof.

### Claim 6 (depends on 1)

The method of claim 1, wherein the immunophilin-binding moiety of the compound is
or a stereoisomeric form thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein RB1 is —SOnB1RB1D, —SOvB1NRB1ARB1B, or —NRB1ASO2RB1D.

### Claim 8 (depends on 1)

The method of claim 1, wherein RB1 is substituted or unsubstituted heterocycloalkyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein R1 is

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 1)

The method of claim 1, wherein L1 is L2-L3-L4-L3-L6;
L2 is connected directly to A;
L2 is-S(O)2—, —N(R2)—, —O—, —S—, —C(O)—, —C(O)N(R2)—, —N(R2)C(O)—, —N(R2)C(O)NH—, —NHC(O)N(R2)—, —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;
L3 is a bond, —S(O)2—, —N(R3)—, —O—, —S—, —C(O)—, —C(O)N(R3)—, —N(R3)C(O)—, —N(R3)C(O)NH—, —NHC(O)N(R3)—, —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;
L4 is a bond, —S(O)2—, —N(R4)—, —O—, —S—, —C(O)—, —C(O)N(R4)—, —N(R4)C(O)—, —N(R4)C(O)NH—, —NHC(O)N(R4)—, —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;
L5 is a bond, —S(O)2—, —N(R5)—, —O—, —S—, —C(O)—, —C(O)N(R5)—, —N(R5)C(O)—, —N(R5)C(O)NH—, —NHC(O)N(R5)—, —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;
L6 is a bond, —S(O)2—, —N(R6)—, —O—, —S—, —C(O)—, —C(O)N(R6)—, —N(R6)C(O)—, —N(R6)C(O)NH—, —NHC(O)N(R6)—, —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
R2, R3, R4, R5, and R6 are independently hydrogen, halogen, —CCl3, —CBr3, —CF3, —CI3, —CH2Cl, —CH2Br, —CH2F, —CH2I, —CHCl2, —CHBr2, —CHF2, —CHI2, —CN, —OH, —NH2, —COOH, —CONH2, —NO2, —SH, —SO3H, —SO4H, —SO2NH2, —NHNH2, —ONH2, —NHC(O)NHNH2, —NHC(O)NH2, —NHSO2H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl3, —OCBr3, —OCF3, —OCI3, —OCH2Cl, —OCH2Br, —OCH2F, —OCH2I, —OCHCl2, —OCHBr2, —OCHF2, —OCHI2, 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.

### Claim 12 (depends on 11)

The method of claim 11, wherein L2 is a substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;
L3 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, or substituted or unsubstituted heterocycloalkylene;
L4 is a bond, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;
L5 is a bond; and
L6 is a bond.

### Claim 13 (depends on 11)

The method of claim 11, wherein L2 is an unsubstituted C3-C7 alkylene, an oxo-substituted C3-C7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene;
L3 is a bond, an unsubstituted C3-C7 alkylene, an oxo-substituted C3-C7 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
L4 is a bond, an unsubstituted C3-C7 alkylene, an oxo-substituted C3-C7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene;
L5 is a bond; and
L6 is a bond.

### Claim 14 (depends on 1)

The method of claim 1, wherein L1 is a bond, an unsubstituted C3-C7 alkylene, an oxo-substituted C3-C7 alkylene, an unsubstituted 3 to 17 membered heteroalkylene, or an oxo-substituted 3 to 17 membered heteroalkylene.

### Claim 15 (depends on 1)

The method of claim 1, wherein R1 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.

### Claim 16 (depends on 1)

The method of claim 1, wherein the immunophilin-binding moiety of the anti-CNS disease drug is
or a stereoisomeric form thereof.

### Claim 17 (depends on 1)

The method of claim 1, wherein the immunophilin-binding moiety of the anti-CNS disease drug is
or a stereoisomeric form thereof.

### Claim 18 (depends on 1)

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.

### Claim 19 (depends on 18)

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

### Claim 20 (depends on 18)

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