# US 10,370,386 B2 · Substituted quinolines as inhibitors of KRAS G12C

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- Number: US 10,370,386 B2
- Document ID: US10370386B2
- Status: Granted
- Kind: B2
- Application number: 15/805,716
- Filed: 2017-11-07
- Published: 2018-05-03
- Granted: 2019-08-06
- Earliest claimed: 2013-10-10
- Assignees: Araxes Pharma LLC
- Applicants: Araxes Pharma LLC
- Inventors: Liansheng Li; Jun Feng; Tao Wu; Pingda Ren; Yi Liu; Yuan Liu; Yun Oliver Long
- Web page: https://patentgrep.com/patent/US10370386B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- C07D 215/46: with hydrocarbon radicals, substituted by nitrogen atoms, attached to said nitrogen atoms
- C07D 215/54: attached in position 3
- C07D 217/22: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D 239/84: Nitrogen atoms
- C07D 239/94: Nitrogen atoms
- C07D 239/95: with hetero atoms directly attached in positions 2 and 4
- C07D 241/44: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, tautomer, prodrug or stereoisomer thereof, wherein R1, R2a, R3a, R3b, R4a, R4b, G1, G2, L1, L2, m1, m2, A, B, W, X, Y, Z and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.

## Claims

### Claim 1

A compound having the following structure (I′) or (I″):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof,
wherein:
is a double or triple bond;
Q is —C(═O)—, —C(═NR8′)—, —NR8C(═O)—, —S(═O)2— or —NR8S(═O)2—;
W is CR6;
X is CR6;
Y is CR6;
Z is N;
L1 is a bond;
L2 is a bond;
R′ is R1 and R″ is R2c; or
R′ is H and R″ is R1;
R1 is heteroaryl;
R2a, R2b and R2C are each independently H, halo, OH, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C3-C8 cycloalkyl, heteroaryl or aryl;
R3a and R3b are, at each occurrence, independently H, OH, NH2, CN, CO2H, halo, C1-C6 alkyl, C2-C6 alkynyl, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R4a and R4b are, at each occurrence, independently H, OH, NH2, CN, CO2H, halo, C1-C6 alkyl, C2-C6 alkynyl, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R6 is, at each occurrence, independently H, CN, NH2, C1-C6 alkyl, C1-C6 alkoxy, CO2NRaRb, cyanoalkyl, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, alkylaminyl, haloalkylaminyl, hydroxyalkylaminyl, amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryl, aryloxy, arylaminyl, arylalkylaminyl or arylalkyloxy;
Ra and Rb are each independently H or C1-C6 alkyl; or
Ra and Rb, together with the nitrogen atom to which they are attached, form a heterocyclyl;
R8 is H, C1-C6 alkyl or hydroxyalkyl;
R8′ is H, OH, CN or C1-C6 alkyl;
R9 is H, CN, CO2H, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxyalkyl; and
R10 is H, CN, CO2H, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, heteroaryl or hydroxyalkyl; or
R9 and R10, together with the carbon atoms to which they are attached, form a cycloalkenyl or heterocyclyl;
wherein each heterocyclyl, heteroaryl, aryl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, alkoxycarbonyl, C3-C8 cycloalkyl, C2-C6 alkynyl, hydroxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, aminylalkylaminyl, aminylcarbonyl, aminylsulfonyl, cycloalkenyl, heterocyclyl, alkylaminyl, haloalkylaminyl, hydroxyalkylaminyl, amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, heterocyclyloxy, heterocyclylalkyloxy, heterocyclylaminyl, heterocyclylalkylaminyl, heteroaryloxy, heteroarylalkyloxy, heteroarylaminyl, heteroarylalkylaminyl, aryloxy, arylaminyl, arylalkylaminyl and arylalkyloxy is optionally substituted with one or more substituents selected from the group consisting of ═O, ═S, CN, OH, NO2, halo, aminyl, imino, aminylsulfonyl, aminylcarbonyl, C1-C12 alkyl, C1-C6 alkoxy, C1-C12 haloalkyl, C1-C6 alkylaminylcarbonyl, aminylcarbonylC1-C6 alkyl, C1-C6 haloalkoxy, C1-C6 alkoxyalkyl, C1-C6 haloalkoxyalkyl, cyanoC1-C6 alkyl, C1-C6 alkylcycloalkyl, C1-C6 alkylheterocycloalkyl, C2-C6 alkynyl, C1-C6 alkylaminyl, C1-C6 alkylcarbonylaminyl, C1-C6 hydroxyalkyl, C2-C6 alkenylcarbonylaminyl, C1-C6 thioalkyl, aryl, aralkyl, C3-C8 cycloalkyl optionally substituted with CN, C3-C8 cycloalkylalkyl, aminylcarbonylC3-C8 cycloalkyl, C3-C8 cycloalkylaminylcarbonyl, C3-C8 fused cycloalkyl, heterocyclylalkyl, heteroarylalkyl, heterocyclyl and heteroaryl;
provided that:
(i) when is a triple bond, then R9 is absent and R10 is H, C1-C6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxyalkyl; and
(ii) when R1 is pyridyl, then at least one of R2a, R2b or R2c is not H.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound has structure (I′):

### Claim 3 (depends on 2)

The compound of claim 2, wherein:
R′ is R1; and
R″ is R2c.

### Claim 4 (depends on 2)

The compound of claim 2, wherein:
R′ is H; and
R″ is R1.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound has structure (I″):

### Claim 6 (depends on 5)

The compound of claim 5, wherein:
R′ is R1; and
R″ is R2c.

### Claim 7 (depends on 5)

The compound of claim 5, wherein:
R′ is H; and
R″ is R1.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Q is —C(═O)—.

### Claim 9 (depends on 1)

The compound of claim 1, wherein
is selected from the group consisting of:

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is substituted with one or more substituents.

### Claim 11 (depends on 10)

The compound of claim 10, wherein the one or more substituents are selected from the group consisting of halo, C1-C6 alkyl, C1-C6 alkoxy and C2-C6 alkenylcarbonylaminyl.

### Claim 12 (depends on 10)

The compound of claim 10, wherein the one or more substituents are selected from the group consisting of fluoro, chloro, methyl and amino.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R1 is thiophenyl, pyridinyl, pyridinonyl, pyrimidinyl, benzooxazolyl, benzoisoxazolyl, benzodioxazolyl, benzoimidazolyl, quinolinyl, quinolinonyl, dihydroquinolinonyl, tetrahydroquinolinyl, quinazolinyl, indazolyl, indolinonyl, benzothiophenyl or dihydrobenzodioxinyl, each optionally substituted.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R1 is selected from the group consisting of:

### Claim 15 (depends on 1)

The compound of claim 1, wherein R2a is halo.

### Claim 16 (depends on 15)

The compound of claim 15, wherein R2a is chloro or fluoro.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R2b is halo.

### Claim 18 (depends on 17)

The compound of claim 17, wherein R2b is chloro or fluoro.

### Claim 19 (depends on 1)

The compound of claim 1, wherein:
R3a is H;
R3b is H;
R4a is H; and
R4b is H.

### Claim 20 (depends on 1)

The compound of claim 1, wherein at least one of R9 and R10 is H.

### Claim 21 (depends on 20)

The compound of claim 20, wherein:
R9 is H; and
R10 is H.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound is selected from the group consisting of:

### Claim 23 (depends on 1)

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

### Claim 24 (depends on 1)

A method for inhibiting RAS-mediated signaling transduction in a subject, the method comprising administering to the subject in need thereof a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

### Claim 25 (depends on 24)

The method of claim 24, wherein the subject has cancer.

### Claim 26 (depends on 25)

The method of claim 25, wherein the cancer is selected from the group consisting of MYH-associated polyposis, pancreatic cancer, colorectal cancer, lung cancer and a hematological cancer.

### Claim 27 (depends on 1)

A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

### Claim 28 (depends on 23)

A method for inhibiting tumor metastasis in a subject, the method comprising administering to the subject in need thereof an effective amount of a pharmaceutical composition of claim 23.

### Claim 29 (depends on 1)

A method for regulating activity of a KRAS G12C, HRAS G12C or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C, HRAS G12C or NRAS G12C mutant protein with a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.

### Claim 30 (depends on 1)

A method for preparing a labeled KRAS G12C, HRAS G12C or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C, HRAS G12C or NRAS G12C mutant protein with a compound of claim 1, or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.