# US 10,501,435 B2 · Substituted quinazoline compounds and uses thereof for modulating glucocerebrosidase activity

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- Number: US 10,501,435 B2
- Document ID: US10501435B2
- Status: Granted
- Kind: B2
- Application number: 16/175,220
- Filed: 2018-10-30
- Published: 2019-02-28
- Granted: 2019-12-10
- Earliest claimed: 2015-07-01
- Assignees: Northwestern University
- Applicants: Northwestern University
- Inventors: Dimitri Krainc; Richard B. Silverman; Jianbin Zheng
- Web page: https://patentgrep.com/patent/US10501435B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/94: Nitrogen atoms
- C07D 401/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/08: Bridged systems
- C07D 495/04: Ortho-condensed systems
- C07D 497/04: Ortho-condensed systems
- C12N 9/2402: {hydrolysing O- and S- glycosyl compounds (3.2.1)}
- C12Y 302/01045: Glucosylceramidase (3.2.1.45), i.e. beta-glucocerebrosidase
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

Disclosed are new small molecules having a substituted quinazoline core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules or activated glucocerebrosidase conjugated to the small molecules, which compositions may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including neurological diseases and disorders such as Gaucher's disease and Parkinson's disease.

## Claims

### Claim 1

A method for treating a disease or disorder that is associated with glucocerebrosidase activity in a subject in need thereof, wherein the disease or disorder is selected from Gaucher's disease and Parkinson's disease, and the method comprises administering to the subject a pharmaceutical composition comprising a pharmaceutical carrier and a compound or a salt or solvate thereof of a Formula I:
wherein:
R1 is hydrogen or C1-C10 alkyl;
n is 0, 1, 2, 3, or 4; and
R2 is hydrogen with the proviso that not both of R1 and R2 are hydrogen, or R2 is a C1-C10 alkyl group which may be straight chain or branched, a C3-C8 cycloalkyl group, a saturated or unsaturated carbon homocycle or heterocycle group comprising one 5- or 6-membered ring or comprising two or three fused 5- or 6-membered rings, a phenoxy group, a C1-C6-branched or straight chain alkyl-phenoxy group, a 2,3-dihydro-1H-indenyl group, a 1,2,3,4-tetrahydro-naphthalenyl group, a C2-C10 straight chain or branched alkenyl group, a C2-C10 straight chain or branched alkynyl group, a polyethylene oxide group, a pyridinoxy group, an indoloxy group, a benzofuranoxy group, or R2 has a formula selected from
wherein R8 is hydrogen, C1-C8 alkoxy, C1-C8 alkyl, halo, or R8 has a formula selected from
p is 1-10 and R9 is amino or R9 has a formula selected from
wherein R10 is H, C1-C6 straight chain or branched alkyl, or a succinimidyl group;
R2 optionally is substituted at one or more positions with a C1-C8 alkyl group, a C1-C8 alkoxy group, a halo group, a phenyl group, a benzyl group, an amino group, a hydroxyl group, a tert-butyloxycarbonyl (BOC) group, a sulfonylmethylphenyl group, a 2,3-dihydro-1,4-benzodioxine-2-carbaldehyde group, a 2,3-dihydromethyl-1,4-benzodioxin group, an imidazole group, a piperazinyl group, a 1-methylpiperazinyl group, a 4-piperazin-1-yl-benzaldehyde group, a 4-(4-methylpiperazin-1-yl)benzaldehyde group, or an azide group; or
optionally where n is 0, R1 and R2 together form a heterocycle comprising one, two, or three 5- or 6-membered rings; and
R3 is pyridinyl, phenyl, thiophenyl, halo, furanyl, or pyrimidinyl, and R3 optionally is substituted at one or more positions with C1-C8 alkyl, halo, amino, or R3 has a formula,
wherein R4 is amino, or R4 has a formula
wherein R5 is —CH2— or —O—CH2—CH2—, and m is 0-4, R6 is H or R6 has a formula
wherein R7 is H, —OH, C1-C8 alkyl, or C1-C8 alkoxy.

### Claim 2

A conjugate comprising a compound of a Formula I covalently attached to glucocerebrosidase:
wherein:
R1 is hydrogen or C1-C10 alkyl;
n is 0, 1, 2, 3, or 4; and
R2 is hydrogen with the proviso that not both of R1 and R2 are hydrogen, or R2 is a C1-C10 alkyl group which may be straight chain or branched, a C3-C8 cycloalkyl group, a saturated or unsaturated carbon homocycle or heterocycle group comprising one 5- or 6-membered ring or comprising two or three fused 5- or 6-membered rings, a phenoxy group, a C1-C6-branched or straight chain alkyl-phenoxy group, a 2,3-dihydro-1H-indenyl group, a 1,2,3,4-tetrahydro-naphthalenyl group, a C2-C10 straight chain or branched alkenyl group, a C2-C10 straight chain or branched alkynyl group, a polyethylene oxide group, a pyridinoxy group, an indoloxy group, a benzofuranoxy group, or R2 has a formula selected from
wherein R8 is hydrogen, C1-C8 alkoxy, C1-C8 alkyl, halo, or R8 has a formula selected from
p is 1-10 and R9 is amino or R9 has a formula selected from
wherein R10 is H, C1-C6 straight chain or branched alkyl, or a succinimidyl group;
R2 optionally is substituted at one or more positions with a C1-C8 alkyl group, a C1-C8 alkoxy group, a halo group, a phenyl group, a benzyl group, an amino group, a hydroxyl group, a tert-butyloxycarbonyl (BOC) group, a sulfonylmethylphenyl group, a 2,3-dihydro-1,4-benzodioxine-2-carbaldehyde group, a 2,3 -dihydromethyl- 1,4-benzodioxin group, an imidazole group, a piperazinyl group, a 1-methylpiperazinyl group, a 4-piperazin-1-yl-benzaldehyde group, a 4-(4-methylpiperazin-1-yl)benzaldehyde group, or an azide group; or
optionally wherein n is 0, R1 and R2 together form a heterocycle comprising one, two, or three 5-or 6-membered rings; and
R3 is pyridinyl, phenyl, thiophenyl, halo, furanyl, or pyrimidinyl, and R3 optionally is substituted at one or more positions with C1-C8 alkyl, halo, amino, or R3 has a formula,
wherein R4 is amino, or R4 has a formula
wherein R5 is —CH2— or —O—CH2—CH2—, and m is 0-4, R6 is H or R6 has a formula
wherein R7 is H, —OH, C1-C8 alkyl, or C1-C8 alkoxy.

### Claim 3 (depends on 2)

A pharmaceutical composition comprising the conjugate of claim 2 and a pharmaceutical carrier.

### Claim 4 (depends on 3)

A method for treating a disease or disorder that is associated with glucocerebrosidase activity in a subject in need thereof, wherein the disease or disorder is selected from Gaucher's disease and Parkinson's disease, and the method comprises administering to the subject the pharmaceutical composition of claim 3.

### Claim 5 (depends on 1)

The method of claim 1, wherein R1 is H and n is 0.

### Claim 6 (depends on 1)

The method of claim 1, wherein R1 is methyl and n is 0.

### Claim 7 (depends on 1)

The method of claim 1, wherein R1 is H and n is 1.

### Claim 8 (depends on 1)

The method of claim 1, wherein R1 is methyl and n is 1.

### Claim 9 (depends on 1)

The method of claim 1, wherein R2 is a saturated or unsaturated carbon homocycle or heterocycle comprising one 5- or 6-membered ring, or a saturated or unsaturated carbon homocycle or heterocycle comprising two or three fused 5- or 6-membered rings, and R2 optionally is substituted at one or more positions with a C1-C8 alkyl group, a C1-C8 alkoxy group, a halo group, a phenyl group, a benzyl group, a tert-butyloxycarbonyl (BOC) group, a sulfonylmethylphenyl group, a 2,3-dihydro-1,4-benzodioxine-2-carbaldehyde group, a 2,3-dihydromethyl-1,4-benzodioxin group, an imidazole group, a piperazine group, a 1-methylpiperazine group, a 4-piperazin-1-yl-benzaldehyde group, a 4-(4-methylpiperazin-1-yl)benzaldehyde group, or an azide group.

### Claim 10 (depends on 1)

The method of claim 1, wherein R2 is selected from the group consisting of

### Claim 11 (depends on 1)

The method of claim 1, wherein R2 is
wherein R8 is hydrogen, C1-C8 alkoxy, C1-C8 alkyl, halo, or R8 has a formula selected from
p is 1-10, and R9 is amino or R9 has a formula selected from
wherein R10is H, C1-C6 straight chain or branched alkyl, or a succinimidyl group.

### Claim 12 (depends on 1)

The method of claim 1, wherein R1 and R2 together form a heterocycle comprising one 5- or 6-membered ring or two or three fused 5- or 6-membered rings.

### Claim 13 (depends on 12)

The method of claim 12, wherein n is 0, R1 and R2 together form a heterocycle selected from

### Claim 14 (depends on 1)

The method of claim 1, wherein R3 is selected from the group consisting of

### Claim 15 (depends on 1)

The method of claim 1, wherein R3 is pyridinyl, optionally pyridine-3-yl, and R3 optionally is substituted at one or more positions with C1-C8 alkyl, halo, and amino.

### Claim 16 (depends on 1)

The method of claim 1, wherein R3 has a formula,
wherein R4 is amino, or R4 has a formula
wherein R5 is —CH2— or —O—CH2—CH2—, and m is 0-4, R6 is H or R6 has a formula
wherein R7 is H, —OH, C1-C8 alkyl, or C1-C8 alkoxy.

### Claim 17 (depends on 2)

The conjugate of claim 2, wherein R1 is H and n is 0.

### Claim 18 (depends on 2)

The method conjugate of claim 2, wherein R2 is a saturated or unsaturated carbon homocycle or heterocycle comprising one 5- or 6-membered ring, or a saturated or unsaturated carbon homocycle or heterocycle comprising two or three fused 5- or 6-membered rings, and R2 optionally is substituted at one or more positions with a C1-C8 alkyl group, a C1-C8 alkoxy group, a halo group, a phenyl group, a benzyl group, a tert-butyloxycarbonyl (BOC) group, a sulfonylmethylphenyl group, a 2,3-dihydro-1,4-benzodioxine-2 -carbaldehyde group, a 2,3-dihydromethyl-1,4-benzodioxin group, an imidazole group, a piperazine group, a 1-methylpiperazine group, a 4-piperazin-1-yl-benzaldehyde group, a 4-(4-methylpiperazin-1-yl)benzaldehyde group, or an azide group.

### Claim 19 (depends on 2)

The conjugate of claim 2, wherein R2 is selected from the group consisting of

### Claim 20 (depends on 2)

The conjugate of claim 2, wherein R2 is
wherein R8 is hydrogen, C1-C8 alkoxy, C1-C8 alkyl, halo, or R8 has a formula selected from
p is 1-10, and R9 is amino or R9 has a formula selected from
wherein R10 is H, C1-C6 straight chain or branched alkyl, or a succinimidyl group.