# US 10,246,424 B2 · Substituted quinazoline compounds and methods of use thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,246,424 B2
- Document ID: US10246424B2
- Status: Granted
- Kind: B2
- Application number: 15/093,951
- Filed: 2016-04-08
- Published: 2016-10-13
- Granted: 2019-04-02
- Earliest claimed: 2015-04-10
- Assignees: Araxes Pharma LLC
- Applicants: Araxes Pharma LLC
- Inventors: Liansheng Li; Jun Feng; Yun Oliver Long; Yuan Liu; Tao Wu; Pingda Ren; Yi Liu
- Web page: https://patentgrep.com/patent/US10246424B2

## CPC

- C07D 239/74: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- C07D 239/94: Nitrogen atoms
- C07D 239/95: with hetero atoms directly attached in positions 2 and 4
- 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 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- 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 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/08: Bridged systems
- C07D 487/10: Spiro-condensed systems
- C07D 491/10: Spiro-condensed systems
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have one of the following structures (I), (II) or (III): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R1, R2a, R2b, R2c, R3a, R3b, R4a, R4b, R5a, R5b, R6, A, B, G1, G2, L1, L2, m1, m2, n, x, y, X 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 a pharmaceutically acceptable salt or stereoisomer or thereof, wherein:
A is N;
G1 and G2 are each independently N or CH;
L1 is a bond or NR7;
L2 is a bond or alkylene;
R1 is aryl or heteroaryl;
R2a, R2b and R2c are each independently H, amino, cyano, halo, hydroxyl, C1-C6 alkyl, C1-C6 alkylaminyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy; C3-C8 cycloalkyl, heterocyclylalkyl, C2-C6 alkynyl, C2-C6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R3a and R3b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R3a and R3b join to form oxo, a carbocyclic or heterocyclic ring; or R3a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R3b joins with R4b to form a carbocyclic or heterocyclic ring;
R4a and R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R4a and R4b join to form oxo, a carbocyclic or heterocyclic ring; or R4a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R4b joins with R3b to form a carbocyclic or heterocyclic ring;
R5a and R5b are, at each occurrence, independently H, hydroxyl, halo or C1-C6 alkyl, or R5a and R5b join to form oxo;
R6 is amino, cyano, substituted alkyl or substituted or unsubstituted: haloalkyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C1-C6 alkylphosphoryl, C1-C6 alkylphosphorylaminyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroarylalkyloxy or heteroarylalkylaminyl when R1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R6 is methyl when R1 is substituted aryl or substituted or unsubstituted heteroaryl;
R7 is, at each occurrence, independently H, C1-C6 alkyl, C3-C8 cycloalkyl or heterocyclyl;
m1 and m2 are each independently 1, 2 or 3;
n is an integer from 0 to 6;
X is a bond, —O—, —NR7— or —S—; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein,
wherein each occurrence of alkyl, alkylene, aryl, heteroaryl, heterocyclyl, alkenyl, alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, alkylphosphoryl, alkylphosphorylaminyl, aminylcarbonyl, alkylaminyl, haloalkyl, alkoxy, haloalkoxy; cycloalkyl, heterocyclylalkyl, heteroarylalkyloxy, heteroarylalkylaminyl and carbocyclic and heterocyclic rings is optionally substituted with one or more substituents unless otherwise specified, the optional substituents being selected from the group consisting of aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C1-C12 alkyl, C1-C6 alkylaminylcarbonyl, aminylcarbonylC1-C6 alkyl, C1-C12 haloalkyl, C1-C6 alkoxy, 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, C3-C8 cycloalkylalkyl, aminylcarbonylC3-C8 cycloalkyl, C3-C8 cycloalkylaminylcarbonyl, C3-C8 fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl, and
wherein: i) each aryl comprises a 6- to 18-membered carbocyclic aromatic ring radical; ii) each heterocyclyl comprises a 3- to 18-membered non-aromatic ring radical having one to twelve ring carbon atoms and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and iii) each heteroaryl comprises a 5- to 14-membered ring radical comprising hydrogen atoms, one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound has the following structure (I′a):
wherein:
represents a double or triple bond;
Q is C(═O)—, —C(═NR8′)—, —NR8C(═O)—, —S(═O)2— or —NR8S(═O)2—;
R8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocycloalkyl;
R8′ is H, —OH, —CN or C1-C6 alkyl;
when is a double bond then R9 and R10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R9 and R10 join to form a carbocyclic, heterocyclic or heteroaryl ring; and
when is a triple bond then R9 is absent and R10 is H, C1-C6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the compound has one of the following structures (I′b), (I′c), (I′d) or (I′e):

### Claim 4 (depends on 1)

The compound claim 1, wherein R1 is aryl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R1 is phenyl or napthyl.

### Claim 6 (depends on 4)

The compound of claim 4, wherein R1 is substituted with one or more substituents.

### Claim 7 (depends on 6)

The compound of claim 6, wherein R1 is substituted with halo, amino, hydroxyl, C1-C6 alkyl, cyano, C1-C6 haloalkyl, C1-C6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, boronic acid, —OC(═O)R, phosphate, phosphoalkoxy or C1-C6 alkylcarbonyloxy, or combinations thereof, wherein R is C1-C6 alkyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R1 is substituted with fluoro, chloro, hydroxyl, methyl, isopropyl, cyclopropryl, trifluoromethyl or methoxy, or combinations thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R1 has one of the following structures:

### Claim 10 (depends on 1)

The compound of claim 1, wherein R1 is heteroaryl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R1 is indazolyl, indolyl, benzoimidazole, benzotriazole or quinolinyl.

### Claim 12 (depends on 10)

The compound of claim 10, wherein R1 is substituted with one or more substituents.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R1 is substituted with hydroxyl, halo or C1-C6 alkyl, or combinations thereof.

### Claim 14 (depends on 10)

The compound of claim 10, wherein R1 has one of the following structures:

### Claim 15 (depends on 1)

The compound of claim 1, wherein R2c is H.

### Claim 16 (depends on 1)

The compound of claim 1, wherein R2a and R2b are each independently halo, haloalkyl, alkyl, or alkoxy.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R2a is fluoro, chloro or methoxy.

### Claim 18 (depends on 1)

The compound of claim 1, wherein R2b is chloro, fluoro or CF3.

### Claim 19 (depends on 1)

The compound of claim 1, wherein n is 0, X is a bond and R6 is heterocyclyl.

### Claim 20 (depends on 19)

The compound of claim 19, wherein R6 is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.

### Claim 21 (depends on 19)

The compound of claim 19, wherein R6 is substituted.

### Claim 22 (depends on 21)

The compound of claim 21, wherein R6 is substituted with C1-C6 alkyl, C1-C6 alkylaminyl, heterocyclyl or spiro-heterocyclyl, or combinations thereof.

### Claim 23 (depends on 19)

The compound of claim 19, wherein R6 has one of the following structures:

### Claim 24 (depends on 1)

The compound of claim 1, wherein n is an integer from 1 to 6, X is —O— and R6 is heterocyclyl or heteroaryl, provided that R6 is not morpholinyl, piperazinyl, pyrrolidinyl or imidazolyl when R1 is indazolyl.

### Claim 25 (depends on 24)

The compound of claim 24, wherein R6 is azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, morpholinyl, morpholinonyl, thiomorpholinyl, or an oxidized analogue thereof, dioxolanyl, or tetrahydropyranyl.

### Claim 26 (depends on 24)

The compound of claim 24, wherein R6 is substituted.

### Claim 27 (depends on 26)

The compound of claim 26, wherein R6 is substituted with oxo, cyano, halo, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy or C1-C6 haloalkyl, heteroaryl, or combinations thereof.

### Claim 28 (depends on 24)

The compound of claim 24, wherein R6 has one of the following structures:

### Claim 29 (depends on 1)

The compound of claim 1, wherein n is an integer from 1 to 6, X is —NR7— and R6 is heterocyclyl or heteroaryl, provided that R6 is not N-methylimidazolyl when R1 is indazolyl.

### Claim 30 (depends on 29)

The compound of claim 29, wherein R6 is piperidinyl, pyridinyl, imidazolyl, pyrrolidinyl, pyrimidinyl, or azetidinyl.

### Claim 31 (depends on 29)

The compound of claim 29, wherein R6 is substituted.

### Claim 32 (depends on 31)

The compound of claim 31, wherein R6 is substituted with halo, hydroxyl, C1-C6 alkyl C3-C8 cycloalkyl, or combinations thereof.

### Claim 33 (depends on 29)

The compound of claim 29, wherein R6 has one of the following structures:

### Claim 34 (depends on 1)

The compound of claim 1, wherein n is 0, X is —O— and R6 is cycloalkyl, heterocyclyl or heteroaryl, provided that R6 is not tetrahydropyranyl or tetrahydrofuranyl when R2a is H and provided that R6 is not N-methylpyrazolyl when R1 is indazolyl.

### Claim 35 (depends on 34)

The compound of claim 34, wherein R6 is cyclohexyl, oxetanyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, azetidinyl, or piperidinyl.

### Claim 36 (depends on 34)

The compound of claim 34, wherein R6 is substituted.

### Claim 37 (depends on 36)

The compound of claim 36, wherein R6 is substituted with hydroxyl, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C1-C6 alkylcarbonyl, heterocyclyl, or combinations thereof.

### Claim 38 (depends on 34)

The compound of claim 34, wherein R6 has one of the following structures:

### Claim 39 (depends on 1)

The compound of claim 1, wherein n is 0, X is —NR7— and R6 is a 3, 4, 6, 7 or 8-membered heterocyclyl or 3, 4, 6 or 7-membered heteroaryl, provided that R6 is not tetrahydropyranyl or N-methylpiperidinyl when R1 is indazolyl; or n is 0, X is —NR7— and R6 is a 5-membered, oxygen-containing heterocyclyl and R1 is aryl.

### Claim 40 (depends on 39)

The compound of claim 39, wherein R6 is piperidinyl, tetrahydrofuranyl, tetrahydrothiopyranyl, or an oxidized analogue thereof, azabicyclo[3.2.1]octanyl, or tetrahydropyranyl.

### Claim 41 (depends on 39)

The compound of claim 39, wherein R6 is substituted.

### Claim 42 (depends on 41)

The compound of claim 41, wherein R6 is substituted with hydroxyl, C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, cycloalkylalky, heterocyclyl, C1-C6 alkylcarbonyl, heteroaryl, or combinations thereof.

### Claim 43 (depends on 39)

The compound of claim 39, wherein R6 has one of the following structures:

### Claim 44 (depends on 1)

The compound of claim 1, wherein R6 is substituted alkyl, and R6 is substituted with one substituent selected from the group consisting of alkylaminylcarbonyl, C2-C6 dialkylaminyl, halo, C1-C6 monoalkylaminyl, heteroarylamino, heteroarylalkyloxy and alkylsulfonyl, and wherein R6 optionally comprises one or more additional substituent.

### Claim 45 (depends on 44)

The compound of claim 44, wherein R6 has one of the following structures:

### Claim 46 (depends on 1)

The compound of claim 1, wherein R6 is alkyl substituted with at least one hydroxyl and X is —O—.

### Claim 47 (depends on 1)

The compound of claim 1, wherein R6 is alkyl substituted with at least one hydroxyl and R1 is aryl or heteroaryl.

### Claim 48 (depends on 1)

The compound of claim 1, wherein R6 is substituted C2-C6 alkyl, X is a bond and n is 0.

### Claim 49 (depends on 48)

The compound of claim 48, wherein R6 is substituted with dialkylaminyl.

### Claim 50 (depends on 1)

The compound of claim 1, wherein R6 is cyano.

### Claim 51 (depends on 1)

The compound of claim 1, wherein R6 is amino, C1-C6 alkylphosphoryl, C1-C6 alkylphosphorylaminyl or perhalomethyl.

### Claim 52 (depends on 51)

The compound of claim 51, wherein R6 has one of the following structures:

### Claim 53

A compound having the following structure (II):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
A is a monocyclic or bicyclic moiety;
B is N;
L1 is a bond or NR5;
L2 is a bond or alkylene;
R1 is aryl or heteroaryl;
R2a, R2b and R2c are each independently H, amino, halo, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylaminyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl; C2-C6 alkynyl, C2-C6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R5 is, at each occurrence, independently H, C1-C6 alkyl, C3-C8 cycloalkyl or heterocyclylalkyl; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein, and
wherein each occurrence of alkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, alkoxyalkyl, aminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, alkylaminyl, haloalkyl, alkoxy, haloalkoxy; cycloalkyl and heterocyclylalkyl is optionally substituted with one or more substituents unless otherwise specified, the optional substituents being selected from the group consisting of aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C1-C12 alkyl, C1-C6 alkylaminylcarbonyl, aminylcarbonylC1-C6 alkyl, C1-C12 haloalkyl, C1-C6 alkoxy, 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, C3-C8 cycloalkylalkyl, aminylcarbonylC3-C8 cycloalkyl, C3-C8 cycloalkylaminylcarbonyl, C3-C8 fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl, and
wherein: i) each aryl comprises a 6- to 18-membered carbocyclic aromatic ring radical; ii) each heterocyclyl comprises a 3- to 18-membered non-aromatic ring radical having one to twelve ring carbon atoms and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and iii) each heteroaryl comprises a 5- to 14-membered ring radical comprising hydrogen atoms, one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.

### Claim 54

A compound having the following structure (III):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
A is CH or N;
B is N;
G1 and G2 are each independently N or CH;
L1 is a bond or NR5;
L2 is a bond or alkylene;
R1 is aryl or heteroaryl;
R2a and R2b are each independently amino, halo, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylaminyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocycyclylalkyl, C2-C6 alkynyl, C2-C6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R2c is H, amino, halo, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkyl amino, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocycyclylalkyl, C2-C6 alkynyl, C2-C6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R3a and R3b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocyclylalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxylalkly, alkoxyalkyl, aminylalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R3a and R3b join to form oxo, a carbocyclic or heterocyclic ring; or R3a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R3b joins with R4b to form a carbocyclic or heterocyclic ring;
R4a and R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, C3-C8 cycloalkyl, heterocyclylalkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, hydroxylalkly, alkoxyalkyl, aminylalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R4a and R4b join to form oxo, a carbocyclic or heterocyclic ring; or R4a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C2-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R4b joins with R3b to form a carbocyclic or heterocyclic ring;
R5 is, at each occurrence, independently H, C1-C6 alkyl, C3-C8 cycloalkyl or heterocyclylalkyl;
x and y are independently integers ranging from 0 to 2; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein,
wherein each occurrence of alkyl, alkylene, aryl, heteroaryl, alkenyl, alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, alkylaminyl, haloalkyl, alkoxy, haloalkoxy; cycloalkyl, heterocyclylalkyl, and carbocyclic and heterocyclic rings is optionally substituted with one or more substituents unless otherwise specified, the optional substituents being selected from the group consisting of aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C1-C12 alkyl, C1-C6 alkylaminylcarbonyl, aminylcarbonylC1-C6 alkyl, C1-C12 haloalkyl, C1-C6 alkoxy, 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-C5 cycloalkyl, C3-C8 cycloalkylalkyl, aminylcarbonylC3-C8cycloalkyl, C3-C5 cycloalkylaminylcarbonyl, C3-C8 fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl, and
wherein: i) each aryl comprises a 6- to 18-membered carbocyclic aromatic ring radical; ii) each heterocyclyl comprises a 3- to 18-membered non-aromatic ring radical having one to twelve ring carbon atoms and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and iii) each heteroaryl comprises a 5- to 14-membered ring radical comprising hydrogen atoms, one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring; and
provided that at least one occurrence of R3a, R3b, R4a or R4b is not H.

### Claim 55 (depends on 2)

The compound of claim 2, wherein Q is —C(═O)—.

### Claim 56 (depends on 1)

The compound of claim 1, wherein E has one of the following structures:

### Claim 57 (depends on 1)

The compound of claim 1, wherein R3a, R3b, R4a and R4b are each H.

### Claim 58 (depends on 1)

The compound of claim 1, wherein the compound has one of the following structures:

### Claim 59 (depends on 1)

A substantially purified atropisomer of the compound of claim 1.

### Claim 60 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 61 (depends on 60)

A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 60 to a subject in need thereof.

### Claim 62 (depends on 53)

The compound of claim 53, having one of the following structures (II′), (II″) or (II′″):
wherein:
A′ is a monocyclic aryl or heteroaryl;
B is N;
G1 and G2 are each independently N or CH;
L1 is a bond or NR5;
L2 is a bond or alkylene;
R1 is aryl or heteroaryl;
R2a, R2b and R2c are each independently H, amino, halo, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkylaminyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, heteroaryl or aryl;
R3a and R3b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl; C1-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R3a and R3b join to form oxo, a carbocyclic or heterocyclic ring; or R3a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, C1-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R3b joins with R4b to form a carbocyclic or heterocyclic ring;
R4a and R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl; C1-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R4a and R4b join to form oxo, a carbocyclic or heterocyclic ring; or R4a is H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C3-C8 cycloalkyl, heterocyclylalkyl, C1-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R4b joins with R3b to form a carbocyclic or heterocyclic ring;
R5 is, at each occurrence, independently H, C1-C6 alkyl, C3-C8 cycloalkyl or heterocycloalkyl;
m1 and m2 are, at each occurrence, independently 1, 2 or 3; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein.

### Claim 63 (depends on 53)

The compound of claim 53, wherein the compound has one of the following structures (II′a), (II″a) or (II′″a):
wherein:
represents a double or triple bond;
Q is —C(═O)—, —C(═NR8′)—, —NR8C(═O)—, —S(═O)2— or —NR8S(═O)2—;
R8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocycloalkyl;
R8′ is H, —OH, —CN or C1-C6 alkyl;
when is a double bond then R9 and R10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R9 and R10 join to form a carbocyclic, heterocyclic or heteroaryl ring; and
when is a triple bond then R9 is absent and R10 is H, C1-C6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

### Claim 64 (depends on 63)

The compound of claim 63, wherein the compound has one of the following structures (II′b), (II′c), (II′d), (II′e), (II′f), (II′g), (II″b), (II″c), (II′″b), (II′″c) or (II′″d):

### Claim 65 (depends on 53)

The compound of claim 53, wherein R1 is aryl.

### Claim 66 (depends on 53)

The compound of claim 53, wherein R1 is heteroaryl.

### Claim 67 (depends on 53)

The compound of claim 53, wherein R1 has one of the following structures:

### Claim 68 (depends on 53)

The compound of claim 53, wherein R2a and R2b are each independently halo, haloalkyl or alkoxy.

### Claim 69 (depends on 53)

The compound of claim 53, wherein A has one of the following structures:

### Claim 70 (depends on 53)

The compound of claim 53, wherein E has one of the following structures:

### Claim 71 (depends on 53)

The compound of claim 53, having one of the following structures:

### Claim 72 (depends on 53)

A pharmaceutical composition comprising a compound of claim 53 and a pharmaceutically acceptable carrier.

### Claim 73 (depends on 72)

A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 72 to a subject in need thereof.

### Claim 74 (depends on 54)

The compound of claim 54, wherein the compound has the following structure (Ma):
wherein:
represents a double or triple bond;
Q is —C(═O)—, —C(═NR8′)—, —NR8C(═O)—, —S(═O)2— or —NR8S(═O)2—;
R8 is H, C1-C6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C3-C8 cycloalkyl or heterocycloalkyl;
R8′ is H, —OH, —CN or C1-C6 alkyl;
when is a double bond then R9 and R10 are each independently H, halo, cyano, carboxyl, C1-C6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R9 and R10 join to form a carbocyclic, heterocyclic or heteroaryl ring; and
when is a triple bond then R9 is absent and R10 is H, C1-C6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.

### Claim 75 (depends on 74)

The compound of claim 74, wherein the compound has one of the following structures (IIIb), (IIIc), (IIId), (IIIe), (IIIf) or (IIIg):

### Claim 76 (depends on 54)

The compound of claim 54, wherein R1 is aryl.

### Claim 77 (depends on 54)

The compound of claim 54, wherein R1 is heteroaryl.

### Claim 78 (depends on 54)

The compound of claim 54, wherein R1 has one of the following structures:

### Claim 79 (depends on 54)

The compound of claim 54, wherein R2a and R2b are each independently halo, haloalkyl or alkoxy.

### Claim 80 (depends on 54)

The compound of claim 54, wherein the compound has one of the following structures:
wherein R3a, R3b, R4a and R4b are independently —OH, —NH2, —CO2H, halo, cyano, unsubstituted C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl.

### Claim 81 (depends on 80)

The compound of claim 80, wherein R3a, R3b, R4a and R4b are independently unsubstituted C1-C6 alkyl, C1-C6 haloalkyl or hydroxylalkly.

### Claim 82 (depends on 54)

The compound of claim 54, wherein E has one of the following structures:

### Claim 83 (depends on 54)

The compound of claim 54, having one of the following structures:

### Claim 84 (depends on 54)

A pharmaceutical composition comprising a compound of claim 54 and a pharmaceutically acceptable carrier.

### Claim 85 (depends on 84)

A method for treatment of a cancer mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 84 to a subject in need thereof.

### Claim 86 (depends on 53)

A substantially purified atropisomer of the compound of claim 53.

### Claim 87 (depends on 54)

A substantially purified atropisomer of the compound of claim 54.

### Claim 88 (depends on 61)

The method of claim 61, wherein the cancer is a pancreatic cancer or a lung cancer.

### Claim 89 (depends on 63)

The method of claim 63, wherein the cancer is a pancreatic cancer or a lung cancer.

### Claim 90 (depends on 85)

The method of claim 85, wherein the cancer is a pancreatic cancer or a lung cancer.