# US 2019/0169127 A1 · Tubulin inhibitors

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- Number: US 2019/0169127 A1
- Document ID: US20190169127A1
- Status: Published application
- Kind: A1
- Application number: 16/211,051
- Filed: 2018-12-05
- Published: 2019-06-06
- Earliest claimed: 2017-12-06
- Assignees: Lin BioScience, LLC
- Applicants: Lin BioScience, LLC
- Inventors: Tom LIN; Cheng-Chi Irene WANG; Jason OLEJNICZAK; Jessica CRISP; Richard TRUONG
- Web page: https://patentgrep.com/patent/US20190169127A1

## CPC

- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- A61P 35/04: specific for metastasis
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compounds, pharmaceutical compositions, and methods of treatment for various diseases, such as cancer. In one aspect, the method comprises the treatment of brain cancers or metastatic cancers that spread to the brain.

## Claims

### Claim 1

A compound of Formula (VIIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:
wherein:
L83 is —C(R83)2C(R83)2C(R83)2—;
E is —C(═O)NR84— or —NR84C(═O)—;
L84 is a bond or —CR86R87—;
Rings D8 and B8 are independently heteroaryl or C2-C8 heterocyclyl;
each R81 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen or —ORa; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
each R82 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
each R83 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, (—NRaC(═O)NRcRd), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl —ORa, or —NRcRd;
R84 is hydrogen, —S(═O)Rb, —S(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —CO2Ra, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
each R85 is independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, (—S(═O)2Rd), —NO2, —NRcRd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd;
or two R85 substituents on the same carbon are taken together to form an oxo;
R86 and R87 are independently hydrogen, halogen, —CN, —ORa, —SRa, —S(═O)Rb, —NO2, —NRcRd, —S(═O)2Rd, —NRaS(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —OC(═O)Rb, —CO2Ra, —OCO2Ra, —C(═O)NRcRd, —OC(═O)NRcRd, —NRaC(═O)NRcRd, —NRaC(═O)Rb, —NRaC(═O)ORa, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd.
Ra is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
Rb is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
each Rc and Rd is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —OH, —OMe, or —NH2; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
or Rc and Rd, together with the nitrogen atom to which they are attached, form a heterocycloalkyl or heteroaryl; wherein the heterocycloalkyl and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —OH, —OMe, or —NH2;
n8 is 1-5;
m8 is 1-4; and
q8 is 1-5.

### Claim 2 (depends on 1)

The compound of claim 1, wherein L84 is a bond.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring D8 is C3-C9 heteroaryl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring D8 is a C3-C9 fused bicyclic ring.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring D8 is selected from the group consisting of:
wherein:
each R88 is independently hydrogen, —S(═O)Rb, —S(═O)2Rd, —S(═O)2NRcRd, —C(═O)Rb, —CO2Rd, —C(═O)NRcRd, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C3-C8 cycloalkyl, C2-C8 heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, and heteroalkyl is optionally substituted with one, two, or three of halogen, —ORa, or —NRcRd; and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted with one, two, or three of halogen, C1-C6 alkyl, C1-C6 haloalkyl, —ORa, or —NRcRd; and
n8 is 0-2.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
Ring B8 is thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiadiazolyl, or oxadiazolyl.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R81 is independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
n8 is 1.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R82 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

### Claim 10 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
m8 is 1.

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R83 is independently hydrogen, halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

### Claim 12 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
R84 is hydrogen or C1-C6 alkyl.

### Claim 13 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
each R85 is independently hydrogen, halogen, amino, —NH2, C1-C6 alkyl, or C1-C6 haloalkyl.

### Claim 14 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein:
q8 is 1 or 2.

### Claim 15 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof wherein the compound is selected from:

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

### Claim 17 (depends on 1)

A method of treating a proliferative disease or disorder in a subject in need thereof, the method comprising administering to the subject a compound of claim 1.

### Claim 18 (depends on 17)

The method of claim 17, wherein the disease or disorder is brain cancer.

### Claim 19 (depends on 17)

The method of claim 17, wherein the disease or disorder is metastatic cancer.

### Claim 20 (depends on 19)

The method of claim 19, wherein the metastatic cancer originates from a primary breast or lung cancer.