# US 2019/0169204 A1 · Benzimidazole derivatives as erbb tyrosine kinase inhibitors for the treatment of cancer

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- Number: US 2019/0169204 A1
- Document ID: US20190169204A1
- Status: Published application
- Kind: A1
- Application number: 16/270,470
- Filed: 2019-02-07
- Published: 2019-06-06
- Earliest claimed: 2014-03-20
- Assignees: Capella Therapeutics, Inc.
- Applicants: Capella Therapeutics, Inc.
- Inventors: Yun Long
- Web page: https://patentgrep.com/patent/US20190169204A1

## CPC

- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 487/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- 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

## Abstract

Provided herein are benzimidazole derivatives, for example, of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a proliferative disease.

## Claims

### Claim 1

A compound of Formula I:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof;
R1 is (a) hydrogen, cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c; or (d) —C(O)CR1e═CR1fCR1g,
—N1aC(O)CR1e═CR1fCR1g,
—S(O)CR1e═CR1fCR1g,
—S(O2)CR1e═CR1fCR1g,
—NR1aS(O)CR1e═CR1fCR1g,
—NR1aS(O2)CR1e═CR1fCR1g, or
R2 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
L1 is a bond, —O—, —S—, —N(R1A)—, or —C(R1AR1B)—, wherein each R1A and R1B is independently hydrogen, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
L2 is C3-10 cycloalkylene, C6-14 arylene, C7-15 aralkylene, heteroarylene, or heterocyclylene;
T is a bond, —O—, —S—, —N═, —N(R4)—, or —C(R4)═;
U is a bond, —O—, —S—, —N═, —N(R5)—, or —C(R5)═;
V is a bond, —O—, —S—, —N═, —N(R6)—, or —C(R6)═;
W is a bond, —O—, —S—, —N═, —N(R7)—, or —C(R7)═;
X and Y are each independently C or N;
Z is NR2A or CR2AR2B, wherein each R2A and R2B is independently hydrogen, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
R4, R5, R6, and R7 are each independently (a) hydrogen, cyano, halo, or nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c; with proviso that at least two of R4, R5, R6, and R7 are not hydrogen; and with the proviso that R4 and R5, R5 and R6, or R6 and R7 are linked together to form heteroaryl or heterocyclyl;
each R1a, R1b, R1c, and R1d is independently hydrogen, C1-6 alkyl, C2-6 alkenyl, R1c, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or R1a and R1c together with the C and N atoms to which they are attached form heterocyclyl; or R1b and R1c together with the N atom to which they are attached form heterocyclyl; and
each R1e, R1f, and R1g is independently hydrogen, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl;
with the proviso that no more than one of T, U, V, and W is a bond;
wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; and (c) —C(O)Ra, —C(O)ORa, —C(O)NRbRc, —C(NRa)NRbRc, —OC(O)Ra, —OC(O)ORa, —OC(O)NRbRc, —OC(═NRa)NRbRc, —OP(O)(ORa)2, —OS(O)Ra, —OS(O)2Ra, —OS(O)NRbRc, —OS(O)2NRbRc, —NRbRc, —NRaC(O)Rd, —NRaC(O)ORd, —NRaC(O)NRbRc, —NRaC(═NRd)NRbRc, —NRaS(O)Rd, —NRaS(O)2Rd, —NRaS(O)NRbRc, —NRaS(O)2NRbRc, —SRa, —S(O)Ra, —S(O)2Ra, —S(O)NRbRc, and —S(O)2NRbRc, wherein each Ra, Rb, Rc, and Rd is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa; or (iii) Rb and Rc together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Qa;
wherein each Qa is independently selected from the group consisting of (a) oxo, cyano, halo, and nitro; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)Rf, —C(O)ORf, —C(O)NRgRh, —C(NRf)NRgRh, —ORf, —OC(O)Rf, —OC(O)ORf, —OC(O)NRgRh, —OC(═NRf)NRgRh, —OP(O)(ORf)2, —OS(O)Rf, —OS(O)2Rf, —OS(O)NRgRh, —OS(O)2NRgRh, —NRgRh, —NRfC(O)Rk, —NRfC(O)ORk, —NRfC(O)NRgRh, —NRfC(=NRk)NRgRh, —NRfS(O)Rk, —NRfS(O)2Rk, —NRfS(O)NRgRh, —NRfS(O)2NRgRh, —SRf, —S(O)Rf, —S(O)2Rf, —S(O)NRgRh, and —S(O)2NRgRh; wherein each Rf, Rg, Rh, and Rk is independently (i) hydrogen; (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) Rg and Rh together with the N atom to which they are attached form heterocyclyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein T is —N═.

### Claim 3 (depends on 1)

The compound of claim 1, wherein T is —C(R4)═.

### Claim 4 (depends on 1, 2, 3)

The compound of any one of claims 1 to 3, wherein U is —N═.

### Claim 5 (depends on 1, 2, 3)

The compound of any one of claims 1 to 3, wherein U is —C(R5)═.

### Claim 6 (depends on 1, 2, 3, 4, 5)

The compound of any one of claims 1 to 5, wherein V is —N═.

### Claim 7 (depends on 1, 2, 3, 4, 5)

The compound of any one of claims 1 to 5, wherein V is —C(R6)═.

### Claim 8 (depends on 1, 2, 3, 4, 5, 6, 7)

The compound of any one of claims 1 to 7, wherein W is —N═.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7)

The compound of any one of claims 1 to 7, wherein W is —C(R7)═.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The compound of any one of claims 1 to 9, wherein X is N.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The compound of any one of claims 1 to 9, wherein X is C.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The compound of any one of claims 1 to 11, wherein Y is N.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11)

The compound of any one of claims 1 to 11, wherein Y is C.

### Claim 14 (depends on 1)

The compound of claim 1, having the structure of Formula II:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

### Claim 15 (depends on 1)

The compound of claim 1, having the structure of Formula III:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof; wherein the symbol
represents that the 6-membered ring contains one N atom in the ring.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The compound of any one of claims 1 to 15, wherein L1 is a bond, —O—, —N(R1A)—, or —C(R1AR1B)—.

### Claim 17 (depends on 16)

The compound of claim 16, wherein L1 is a bond.

### Claim 18 (depends on 16)

The compound of claim 16, wherein L1 is —O—.

### Claim 19 (depends on 16)

The compound of claim 16, wherein L1 is NH or CH2.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

The compound of any one of claims 1 to 19, wherein L2 is C3-10 cycloalkylene, heteroarylene, or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

### Claim 21 (depends on 20)

The compound of claim 20, wherein L2 is heteroarylene or heterocyclylene, each of which is optionally substituted with one or more substituents Q.

### Claim 22 (depends on 70)

The comnniind of claim 70 wherein T 2 is:
wherein:
r is an integer of 0, 1, 2, 3, 4, 5, or 6;
s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
each RL is independently (i) hydrogen; or (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(=NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c; or
two RL together, when there are two or more RL attached to the same ring, are linked together to form (i) a bond, —O—, —NRN—, or —S—; or (ii) C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

### Claim 23 (depends on 20)

The compound of claim 20, wherein L2 is:
wherein:
r is an integer of 0, 1, 2, 3, 4, 5, or 6;
s is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
each RL is independently (i) hydrogen; or (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —Or1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(=NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR11S(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c; or
two RL together, when there are two or more RL attached to the same ring, are linked together to form (i) a bond, —O—, —NRN—, or —S—; or (ii) C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

### Claim 24 (depends on 20)

The compound of claim 20, wherein L2 is:
wherein:
r is an integer of 0, 1, 2, 3, 4, 5, or 6;
t is an integer of 0, 1, 2, 3, 4, 5, or 6; and
each RL is independently (i) hydrogen; or (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR″, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c; or
two RL together, when there are two or more RL attached to the same ring, are linked together to form (i) a bond, —O—, —NRN—, or —S—; or (ii) C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

### Claim 25 (depends on 20)

The compound of claim 20, wherein L2 is:
wherein:
r is an integer of 0, 1, 2, 3, 4, 5, or 6;
t is an integer of 0, 1, 2, 3, 4, 5, or 6; and
each RL is independently (i) hydrogen; or (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c; or
two RL together, when there are two or more RL attached to the same ring, are linked together to form (i) a bond, —O—, —NRN—, or —S—; or (ii) C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q.

### Claim 26 (depends on 22, 23, 24, 25)

The compound of any one of claims 22 to 25, wherein r is 0.

### Claim 27 (depends on 20)

The compound of claim 20, wherein L1-L2 is:
wherein the symbol
represents that the 6-membered ring contains one to three N atoms in the ring, and each sulfur is optionally oxidized as sulfoxide or sulfone.

### Claim 28 (depends on 20)

The compound of claim 20, wherein L1-L2 is:

### Claim 29 (depends on 1)

The compound of claim 1, having the structure of Formula IV:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:
m is an integer of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
n is an integer of 0, 1, 2, 3, 4, 5, or 6;
each RL is independently (i) hydrogen; or (ii) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (iii) —C(O)R1a, —C(O)OR1a, —C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(═NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —SR1a, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c; or
two RL together, when there are two or more RL attached to the same ring, are linked together to form (i) a bond, —O—, —NRN—, or —S—; or (ii) C1-6 alkylene, C1-6 heteroalkylene, C2-6 alkenylene, or C2-6 heteroalkenylene, each of which is optionally substituted with one or more substituents Q; and
RN is (a) hydrogen; (b) C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; (c) —C(O)OR1a, C(O)NR1bR1c, —C(NR1a)NR1bR1c, —OR1a, —OC(O)R1a, —OC(O)OR1a, —OC(O)NR1bR1c, —OC(NR1a)NR1bR1c, —OS(O)R1a, —OS(O)2R1a, —OS(O)NR1bR1c, —OS(O)2NR1bR1c, —NR1bR1c, —NR1aC(O)R1d, —NR1aC(O)OR1d, —NR1aC(O)NR1bR1c, —NR1aC(═NR1d)NR1bR1c, —NR1aS(O)R1d, —NR1aS(O)2R1d, —NR1aS(O)NR1bR1c, —NR1aS(O)2NR1bR1c, —S(O)R1a, —S(O)2R1a, —S(O)NR1bR1c, or —S(O)2NR1bR1c.

### Claim 30 (depends on 1)

The compound of claim 1, having the structure of Formula V:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

### Claim 31 (depends on 1)

The compound of claim 1, having the structure of Formula VI:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

### Claim 32 (depends on 1)

The compound of claim 1, having the structure of Formula VII:
or a single enantiomer, a racemic mixture, a mixture of diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The compound of any one of claims 1 to 32, wherein R1 is —C(O)CR1e═CR1fCR1g or

### Claim 34 (depends on 33)

The compound of claim 33, wherein R1 is selected from:

### Claim 35 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The compound of any one of claims 1 to 32, wherein R1 is —N1aC(O)CR1e═CR1fCR1g or

### Claim 36 (depends on 35)

The compound of claim 35, wherein R1 is selected from:

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)

The compound of any one of claims 1 to 36, wherein R2 is C6-14 aryl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.

### Claim 38 (depends on 37)

The compound of claim 37, wherein R2 is 6- to 10-membered monocyclic or bicyclic aryl, optionally substituted with one or more substituents Q.

### Claim 39 (depends on 37)

The compound of claim 37, wherein R2 is 5- to 10-membered monocyclic or bicyclic heteroaryl comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents Q.

### Claim 40 (depends on 37)

The compound of claim 37, wherein R2 is 5- to 10-membered monocyclic or bicyclic heterocyclic comprising 1 to 4 heteroatoms selected from N, O, and S, optionally substituted with one or more substituents Q.

### Claim 41 (depends on 37)

The compound of claim 37, wherein R2 is phenyl, pyridinyl, pyridazinyl, benzo[c][1,2,5]oxodiazolyl, or benzo[c][1,2,5]thiodiazolyl, each of which is optionally substituted with one or more substituents Q.

### Claim 42 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41)

The compound of any one of claims 1 to 41, wherein R4 is hydrogen.

### Claim 43 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The compound of any one of claims 1 to 42, wherein R5 and R6 are linked together to form heterocyclyl, optionally substituted with one or more substituents Q.

### Claim 44 (depends on 44)

The compound of claim 44, wherein R5 and R6 are linked together to form heterocyclyl selected from:

### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The compound of any one of claims 1 to 44, wherein R7 is hydrogen.

### Claim 46 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The compound of any one of claims 1 to 44, wherein R7 is chloro, methyl, or methoxy.

### Claim 47 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42)

The compound of any one of claims 1 to 42, wherein R6 and R7 are linked together to form heterocyclyl, optionally substituted with one or more substituents Q.

### Claim 48 (depends on 47)

The compound of claim 47, wherein R6 and R7 are linked together to form heterocyclyl selected from:
wherein p is an integer of 1, 2, 3, 4, 5, or 6.

### Claim 49 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 47)

The compound of any one of claims 1 to 42, 47, and 48, wherein R5 is hydrogen.

### Claim 50 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49)

The compound of any one of claims 1 to 49, wherein Z is NH.

### Claim 51 (depends on 1)

The compound of claim 1, selected from:
and single enantiomers, racemic mixtures, mixtures of diastereomers, and isotopic variants thereof and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

### Claim 52 (depends on 1)

The compound of claim 1, selected from:
and single enantiomers, racemic mixtures, mixtures of diastereomers, and isotopic variants thereof and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

### Claim 53 (depends on 51, 52)

The compound of claim 51 or 52, wherein R1a is hydrogen or methyl.

### Claim 54 (depends on 51, 52, 53)

The compound of any one of claims 51 to 53, wherein R1f is hydrogen, dimethylaminomethyl, pyrrolidin-1-ylmethyl, or piperidin-1-ylmethyl.

### Claim 55 (depends on 1)

The compound of claim 1, selected from:
and isotopic variants thereof and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

### Claim 56 (depends on 1)

The compound of claim 1, selected from:
and isotopic variants thereof and pharmaceutically acceptable salts, solvates, and prodrugs thereof.

### Claim 57 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56)

A pharmaceutical composition comprising the compound of any one of claims 1 to 56, and a pharmaceutically acceptable excipient.

### Claim 58 (depends on 57)

The pharmaceutical composition of claim 57, wherein the composition is formulated for oral, nasal, bronchial, or topical administration.

### Claim 59 (depends on 57, 58)

The pharmaceutical composition of claim 57 or 58, wherein the composition is formulated as a single dosage form.

### Claim 60 (depends on 57, 58, 59)

The pharmaceutical composition of any one of claims 57 to 59, wherein the composition is formulated as oral, parenteral, nasal, respiratory, pulmonary, or intravenous dosage form.

### Claim 61 (depends on 60)

The pharmaceutical composition of claim 60, wherein the pharmaceutical composition is in an oral dosage form.

### Claim 62 (depends on 61)

The pharmaceutical composition of claim 61, wherein the oral dosage form is a tablet or capsule.

### Claim 63 (depends on 57, 58, 59, 60, 61, 62)

The pharmaceutical composition of any one of claims 57 to 62, further comprising a second therapeutic agent.

### Claim 64 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63)

A method for treating, preventing, or ameliorating one or more symptoms of an ERBB-mediated condition, disorder, or disease in a subject, comprising administering to the subject the compound of any one of claims 1 to 56 or the pharmaceutical composition of any one of claims 57 to 63.

### Claim 65 (depends on 64)

The method of claim 64, wherein the ERBB-mediated condition, disorder, or disease is a proliferative disease.

### Claim 66 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63)

A method for treating, preventing, or ameliorating one or more symptoms of a proliferative or disease in a subject, comprising administering to the subject the compound of any one of claims 1 to 56 or the pharmaceutical composition of any one of claims 57 to 63.

### Claim 67 (depends on 65, 66)

The method of claim 65 or 66, wherein the proliferative disease is cancer.

### Claim 68 (depends on 67)

The method of claim 67, wherein the cancer is drug-resistant.

### Claim 69 (depends on 67, 68)

The method of claim 67 or 68, wherein the cancer contains an ERBB variant.

### Claim 70 (depends on 69)

The method of claim 69, wherein the ERBB variant is an EGFR variant.

### Claim 71 (depends on 70)

The method of claim 70, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863.

### Claim 72 (depends on 70)

The method of claim 70, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 719, 746-751, 790, and 858.

### Claim 73 (depends on 70)

The method of claim 70, wherein the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S. G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R.

### Claim 74 (depends on 70)

The method of claim 70, wherein the EGFR variant contains T790M, L858R, or a combination thereof.

### Claim 75 (depends on 69)

The method of claim 69, wherein the ERBB variant is a HER2 variant.

### Claim 76 (depends on 67, 68, 69, 70, 71, 72, 73, 74, 75)

The method of any one of claims 67 to 75, wherein the HER2 is overexpressed in the cancer.

### Claim 77 (depends on 68, 69, 70, 71, 72, 73, 74, 75, 76)

The method of any one of claims 68 to 76, wherein the cancer is resistant to an EGFR inhibitor.

### Claim 78 (depends on 77)

The method of claim 77, wherein the cancer is resistant to afatinib, canertinib, dacomitinib, erlotinib, gefitinib, icotinib, lapatinib, neratinib, pelitinib, varlitinib, or a combination thereof.

### Claim 79 (depends on 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78)

The method of any one of claims 67 to 78, wherein the cancer is bladder cancer, brain tumor, breast cancer, cancer of the mouth and throat, colorectal cancer, lung cancer, or pancreatic cancer, prostate cancer, stomach cancer, or uterine cancer.

### Claim 80 (depends on 79)

The method of claim 79, wherein the cancer is lung cancer.

### Claim 81 (depends on 79)

The method of claim 79, wherein the cancer is non-small cell lung cancer.

### Claim 82 (depends on 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81)

The method of any one of claims 67 to 81, wherein the cancer is relapsed or refractory.

### Claim 83 (depends on 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82)

The method of any one of claims 64 to 82, wherein the subject is a human.

### Claim 84 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56)

A method of inhibiting the growth of a cell, comprising contacting the cell with the compound of any one of claims 1 to 56.

### Claim 85 (depends on 84)

The method of claim 84, wherein the cell is cancer cell.

### Claim 86 (depends on 84, 85)

The method of claim 84 or 85, wherein the cell contains an ERBB variant.

### Claim 87 (depends on 86)

The method of claim 86, wherein the ERBB variant is an EGFR variant.

### Claim 88 (depends on 87)

The method of claim 87, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863.

### Claim 89 (depends on 87)

The method of claim 87, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 719, 746-751, 790, and 858.

### Claim 90 (depends on 87)

The method of claim 87, wherein the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S. G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R.

### Claim 91 (depends on 87)

The method of claim 87, wherein the EGFR variant contains T790M, L858R, or a combination thereof.

### Claim 92 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56)

A method of modulating the activity of an ERBB, comprising contacting the ERBB with the compound of any one of claims 1 to 56.

### Claim 93 (depends on 92)

The method of claim 92, wherein the ERBB is an ERBB variant.

### Claim 94 (depends on 93)

The method of claim 93, wherein the ERBB variant is an EGFR variant.

### Claim 95 (depends on 94)

The method of claim 94, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 689, 700, 709, 715, 719, 720, 746-759, 761-765, 767-775, 783, 784, 790, 796, 826, 839, 846, 858, 861, and 863.

### Claim 96 (depends on 94)

The method of claim 94, wherein the EGFR variant contains one or more deletions, insertions, or substitutions at the amino acid positions of 719, 746-751, 790, and 858.

### Claim 97 (depends on 94)

The method of claim 94, wherein the EGFR variant contains one, two, or more deletions, insertions, and/or substitutions, each independently selected from G719C, G719S. G719A, ΔE746-A750, ΔE746-T751, ΔE746-A750 (ins RP), ΔD761-E762 (ins EAFQ), ΔS768-D770 (dup SVD), ΔV769-D770 (ins ASV), ΔD770-N771 (ins SVQ), ΔP772-H773 (ins PR), ΔH773-V774 (ins NPH), ΔH773-V774 (ins H), ΔH773-V774 (ins PH), and ΔH773-V774 (ins GNPH), T790M, and L858R.

### Claim 98 (depends on 94)

The method of claim 94, wherein the EGFR variant contains T790M, L858R, or a combination thereof.