# US 2020/0399269 A1 · [1,2,4]triazolo[1,5-a] pyrimidine compounds and use in stabilizing microtubules

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- Number: US 2020/0399269 A1
- Document ID: US20200399269A1
- Status: Published application
- Kind: A1
- Application number: 16/977,643
- Filed: 2019-02-28
- Published: 2020-12-24
- Earliest claimed: 2018-03-02
- Assignees: The Trustees of the University of Pennsylvania; The Regents of the University of California
- Applicants: The Trustees of the University of Pennsylvania; The Regents of the University of California
- Inventors: Kurt R. BRUNDEN; Virginia M.Y. LEE; John Q. TROJANOWSKI; Carlo BALLATORE; Killian OUKOLOFF; Amos B. SMITH, III
- Web page: https://patentgrep.com/patent/US20200399269A1

## CPC

- A61P 35/00: Antineoplastic agents
- C07D 471/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- 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
- C07D 487/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present disclosure provides compounds of formula (I) or (II) or a pharmaceutically acceptable salt or stereoisomer thereof, wherein Rx-R8 are defined herein. Also provided are compositions comprising a compound described herein and a pharmaceutically effective excipient, methods of stabilizing microtubules in a patient comprising administering to the patient a microtubule-stabilizing amount of a compound described herein, methods of treating cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein, and methods of treating a neurodegenerative disease in a patient comprising administering to the patient a therapeutically effective amount of a compound described herein.

## Claims

### Claim 1

A compound of formula (I) or formula (II):
wherein:
R1 is H, Br, Cl, or F;
R2 is H, C1-6alkyl, or substituted C1-6alkyl;
R3 is diazirinyl, C1-6alkyl, halogenated C1-6alkyl, C1-6alkyl substituted with diazirinyl, aryl substituted with diazirinyl, or C(O)(aryl substituted with diazirinyl);
R4 is H, Br, Cl, or F;
R5 is H, Br, Cl, or F;
R6 is halogen, C1-6alkoxy, or substituted C1-6alkoxy;
R7 is H, C1-6alkyl, or halogenated C1-6alkyl; and
R8 is —O—C1-6alk-NR9—C(O)-aryl substituted by diazirinyl or —O-substituted C1-6 alk-NR9—C(O)-aryl substituted by diazirinyl, wherein R9 is H or C1-6alkyl;
or a pharmaceutically acceptable salt or stereoisomer thereof.

### Claim 2 (depends on 1)

The compound of claim 1, that is of formula (I):

### Claim 3 (depends on 1, 2)

The compound of claim 1 or 2, wherein R1 is H.

### Claim 4 (depends on 1, 2)

The compound of claim 1 or 2, wherein R1 is Br, Cl, or F, preferably Cl.

### Claim 5 (depends on 2)

The compound of claim 2, wherein R2 is H.

### Claim 6 (depends on 2)

The compound of claim 2, wherein R2 is C1-6alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.

### Claim 7 (depends on 2)

The compound of claim 2, wherein R2 is substituted C1-6alkyl.

### Claim 8 (depends on 1, 2)

The compound of claim 1 or 2, wherein R3 is C1-6alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.

### Claim 9 (depends on 2)

The compound of claim 2, wherein R3 is halogenated C1-6alkyl such as CH2CF3, CH2CH2CF3, CH(CH3)(CF3), CH2CH2CH2CF3, CH2CH(CF3)CH3, or CH(CF3)CH2CH3, preferably CH(CH3)CF3.

### Claim 10 (depends on 2)

The compound of claim 2, wherein R3 is diazirinyl such as
wherein R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 11 (depends on 2)

The compound of claim 2, wherein R3 is C1-6alkyl substituted with diazirinyl such as
wherein R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 12 (depends on 2)

The compound of claim 2, wherein R3 is aryl substituted with diazirinyl such as phenyl substituted with diazirinyl, such as
wherein R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 13 (depends on 2)

The compound of claim 2, wherein R3 is C(O)(aryl substituted with diazirinyl) such as phenyl substituted with diazirinyl, such as
wherein R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 14 (depends on 2)

The compound of claim 2, wherein R6 is halogen such as Br, Cl, or F, preferably F.

### Claim 15 (depends on 2)

The compound of claim 2, wherein R6 is C1-6alkoxy such as methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.

### Claim 16 (depends on 2)

The compound of claim 2, wherein R6 is C1-6alkoxy substituted with diazirinyl such as
wherein R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 17 (depends on 1)

The compound of claim 1, that is of formula (II):

### Claim 18 (depends on 17)

The compound of claim 17, wherein R1 is H.

### Claim 19 (depends on 17)

The compound of claim 17, wherein R1 is Br, Cl, or F, preferably Cl.

### Claim 20 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R2 is H.

### Claim 21 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R2 is C1-6alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.

### Claim 22 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R2 is substituted C1-6alkyl.

### Claim 23 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R7 is H.

### Claim 24 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R7 is C1-6alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.

### Claim 25 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R7 is halogenated C1-6alkyl such as CH2CF3, CH2CH2CF3, CH(CH3)(CF3), CH2CH2CH2CF3, CH2CH(CF3)CH3, or CH(CF3)CH2CH3, preferably CH(CH3)CF3.

### Claim 26 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R8 is —O—C1-6alk-NR9—C(O)-aryl substituted by diazirinyl such as
wherein R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 27 (depends on 17, 18, 19)

The compound of any one of claims 17 to 19, wherein R8 is —O-substituted C1-6alk-C(O)-aryl substituted by diazirinyl such as
wherein R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 28 (depends on 26)

The compound of claim 26, wherein R10 is H.

### Claim 29 (depends on 26)

The compound of claim 26, wherein R10 is C1-6alkyl such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.

### Claim 30 (depends on 1, 2)

The compound of claim 1 or 2, wherein R4 is H.

### Claim 31 (depends on 1, 2)

The compound of claim 1 or 2, wherein R4 is Br, Cl, or F, preferably F.

### Claim 32 (depends on 1, 2)

The compound of claim 1 or 2, wherein R5 is H.

### Claim 33 (depends on 1, 2)

The compound of claim 1 or 2, wherein R5 is Br, Cl, or F, preferably F.

### Claim 34 (depends on 1)

The compound of claim 1, which is of formula (IA):
wherein, R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 35 (depends on 1)

The compound of claim 1, which is of formula OK
wherein:
R10 is H, C1-6alkyl, or halogenated C1-6alkyl;
R11 is H, C1-6alkyl, or halogenated C1-6alkyl; and
R12 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 36 (depends on 1)

The compound of claim 1, which is of formula (IIA):
wherein:
R9 is H, C1-6alkyl, or substituted C1-6alkyl; and
R10 is H, C1-6alkyl, or halogenated C1-6alkyl.

### Claim 37 (depends on 1)

The compound of claim 1, that is:

### Claim 38 (depends on 1)

The compound of claim 1, that is:

### Claim 39 (depends on 1)

The compound of claim 1, that is:

### Claim 40 (depends on 1, 2)

A composition comprising a compound of claim 1 or 2 and a pharmaceutically acceptable excipient.

### Claim 41 (depends on 1, 2)

A method of stabilizing microtubules in a patient comprising administering to the patient a microtubule-stabilizing amount of a compound of claim 1 or 2.

### Claim 42 (depends on 41)

The method of claim 41, wherein the patient has a disease that is a neurodegenerative disease or cancer.

### Claim 43 (depends on 1, 2)

A method of treating a neurodegenerative disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or 2.

### Claim 44 (depends on 43)

The method of claim 43, wherein the neurodegenerative disease is characterized by a tauopathy or compromised microtubule function in the brain of the patient.

### Claim 45 (depends on 43)

The method of claim 43, wherein the neurodegenerative disease is Alzheimer's disease, frontotemporal lobar degeneration, Pick's disease, progressive supranuclear palsy (PSP), corticobasal degeneration, Parkinson's disease (PD), PD with dementia, Lewy body disease with dementia, or amyotrophic lateral sclerosis.

### Claim 46 (depends on 43)

The method of claim 43, wherein the neurodegenerative disease is traumatic brain injury, in particular, repetitive traumatic brain injury and chronic traumatic encephalopathy, or post-traumatic stress disorder.

### Claim 47 (depends on 43)

The method of claim 43, wherein the neurodegenerative disease is schizophrenia.

### Claim 48 (depends on 1, 2)

A method of treating a cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or 2.

### Claim 49 (depends on 48)

The method of claim 48, wherein the cancer is breast cancer, uterine cancer, lung cancer, ovarian cancer, and skin cancer, or non-Hodgkin's lymphoma.