# US 11,028,083 B2 · Ethanediamine-heterocycle derivatives as inhibitors of protein arginine methyltransferases

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

- Number: US 11,028,083 B2
- Document ID: US11028083B2
- Status: Granted
- Kind: B2
- Application number: 16/290,675
- Filed: 2019-03-01
- Published: 2019-09-05
- Granted: 2021-06-08
- Earliest claimed: 2018-03-01
- Assignees: Board of Regents, The University of Texas System
- Applicants: Board of Regents, The University of Texas System
- Inventors: Maria Emilia Di Francesco; Philip Jones; Timothy Joseph McAfoos
- Web page: https://patentgrep.com/patent/US11028083B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 35/02: specific for leukemia
- C07D 487/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention relates to ethanediamine-heterocycle compounds that are able to act as inhibitors of PRMTs (protein arginine methyltransferases) for treating cancer and other diseases mediated by PRMTs.

## Claims

### Claim 1

A compound of structural Formula I
or a salt thereof, wherein:
A is a monocyclic heterocycloalkyl ring comprising 5 to 7 ring members including:
X1 and X2,
Z, which is chosen from —CH2—, —CHR3—, —C(R3)2—, —N(R5a)—, N(COR5a)—,
N(CONR5aR5b)—, N(SO2R5a)—, —O—, and —SO2—, and
all other ring members Y, which are chosen from —CH2—, —CHR2—, and —C(R2)2—;
R1a, R1b, and R1c are independently chosen from H and CH3;
either X1 is C and X2 is N, or X1 is N and X2 is C;
each R2 and R3 is independently chosen from cyano, halo, hydroxy, C1-6alkyl,
C1-6haloalkyl, C1-6hydroxyalkyl, (C1-6alkoxy)C1-6 alkyl; OR5a, C(O)R5a, C(O)OR5a, C(O)NR5aR5b, SO2R5a; SO2NR5aR5b, NR5aR5b, NR5aC(O)R5b, NR5cC(O)OR5b, NR5cC(O)NR5aR5b, and NR5aSO2R5b, or
any two R2 or R3, when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R4 is chosen from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, any of which is optionally substituted with 1, 2, 3, or 4 R6 groups;
each R5a and R5b is independently chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, (C1-6alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl, or
R5a and R5b, when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R5c is chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, (C1-6 alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl;
each R6 is independently chosen from C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, (C1-6 alkoxy)C1-6 alkyl, (haloC1-6alkoxy)C1-6alkyl, C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, (C3-6 alkoxy)C3-6 cycloalkyl, (C3-6 cycloalkyl)C1-6alkyl, (heterocycloalkyl)C1-6alkyl, (aryl)C1-6alkyl, (heteroaryl)C1-6alkyl, ((C1-6alkyl)aryl)C1-6alkyl, ((C1-6alkyl)heteroaryl)C1-6alkyl, OR7, CH2OR7, CH2CH2OR7, COR7, COOH, COOR7, CONH2, CONHR7, CON(R7)2, NHCOR7, NR7COR7, NHCONH2, NHCONHR7, NHCON(R7)2, NR7CONH2, NR7CONHR7, NR7CON(R7)2, SO2R7, SO2NHR7, SO2N(R7)2, NHSO2R7, NR7SO2R7, carboxy, cyano, halo, hydroxy, and oxo;
each R7 is independently chosen from C1-6alkyl, haloC1-6alkyl, aryl, heteroaryl, C3-6cycloalkyl, heterocycloalkyl, (aryl)C1-6alkyl, (heteroaryl)C1-6 alkyl, (cycloalkyl)C1-6alkyl, and (heterocycloalkyl)C1-6 alkyl, any of which is optionally substituted with 1 or 2 R8 groups; and
each R8 is independently chosen from C1-6 alkyl, haloC1-6 alkyl, C3-6 cycloalkyl, and haloC3-6 cycloalkyl.

### Claim 2 (depends on 1)

The compound as recited in claim 1, or a salt thereof, wherein A comprises 5 or 6 ring members.

### Claim 3 (depends on 2)

The compound as recited in claim 2, or a salt thereof, wherein each Y is —CH2—.

### Claim 4 (depends on 3)

The compound as recited in claim 3, or a salt thereof, wherein Z is chosen from —CH2—, —CHOH—, —CH(CF3), —C(CH3)2—,
—N(R5a)—, —N(COR5a)—, —CH(CH2OH)—, —CF2—, and —O—.

### Claim 5 (depends on 4)

The compound as recited in claim 4, or a salt thereof, wherein Z is chosen from —CH2—, —C(CH3)2—,
—CF2—, and —O—.

### Claim 6 (depends on 5)

The compound as recited in claim 5, or a salt thereof, wherein R4 is chosen from cycloalkyl and heterocycloalkyl, either of which is optionally substituted with 1, 2, or 3 R6 groups.

### Claim 7 (depends on 6)

The compound as recited in claim 6, or a salt thereof, wherein at least one of R1b and R1c is H.

### Claim 8 (depends on 7)

The compound as recited in claim 7, or a salt thereof, wherein each R6 is independently chosen from C1-6alkyl, haloC1-6alkyl, (C1-6 alkoxy)C1-6alkyl, (aryl)C1-6alkyl, COR7, COOR7, CONHR7, CON(R7)2, NHCOR7, SO2R7, NHSO2R7, halo, hydroxy, and oxo.

### Claim 9 (depends on 8)

The compound as recited in claim 8, or a salt thereof, wherein each R7 is independently chosen from C1-6alkylo, C3-6 cycloalkyl, (aryl)C1-6alkyl, and (heteroaryl)C1-6alkyl, any of which is optionally substituted with 1 or 2 R8 groups.

### Claim 10 (depends on 9)

The compound as recited in claim 9, or a salt thereof, wherein X1 is N and X2 is C.

### Claim 11 (depends on 1)

The compound as recited in claim 1, having structural Formula II
or a salt thereof, wherein:
A is a monocyclic heterocycloalkyl ring comprising 5 to 7 ring members including:
X1 and X2,
Z, which is chosen from —CH2—, —CHR3—, —C(R3)2—, —N(R5a)—, N(COR5a)—,
N(CONR5aR5b)—, N(SO2R5a)—, —O—, and —SO2—, and
all other ring members Y, which are chosen from —CH2—, —CHR2—, and —C(R2)2—;
R1a, R1b, and R1c are independently chosen from H and CH3;
either X1 is C and X2 is N, or X1 is N and X2 is C;
each R2 and R3 is independently chosen from cyano, halo, hydroxy, C1-6alkyl,
C1-6haloalkyl, C1-6hydroxyalkyl, (C1-6alkoxy)C1-6 alkyl; OR5a, C(O)R5a, C(O)OR5a, C(O)NR5aR5b, SO2R5a; SO2NR5aR5b, NR5aR5b, NR5aC(O)R5b, NR5cC(O)OR5b, NR5cC(O)NR5aR5b, and NR5a SO2R5b, or
any two R2 or R3, when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R4a and R4b, together with the atom to which they are attached, form a cycloalkyl or heterocycloalkyl ring, which is optionally substituted with 1, 2, or 3 R6 groups;
each R5a and R5b is independently chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl, or
R5a and R5b, when attached directly to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R5c is chosen from H, C1-6alkyl, cyanoC1-6 alkyl, haloC1-6alkyl, hydroxyC1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl;
each R6 is independently chosen from C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6 alkyl, (C1-6alkoxy)C1-6 alkyl, (haloC1-6 alkoxy)C1-6 alkyl, C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, (C3-6 alkoxy)C3-6 cycloalkyl, (C3-6 cycloalkyl)C1-6alkyl, (heterocycloalkyl)C1-6alkyl, (aryl)C1-6 alkyl, (heteroaryl)C1-6 alkyl, ((C1-6 alkyl)aryl)C1-6 alkyl, ((C1-6alkyl)heteroaryl)C1-6alkyl, OR7, CH2OR7, CH2CH2OR7, COR7, COOH, COOR7, CONH2, CONHR7, CON(R7)2, NHCOR7, NR7COR7, NHCONH2, NHCONHR7, NHCON(R7)2, NR7CONH2, NR7CONHR7, NR7CON(R7)2, SO2R7, SO2NHR7, SO2N(R7)2, NHSO2R7, NR7SO2R7, carboxy, cyano, halo, hydroxy, and oxo;
each R7 is independently chosen from C1-6alkyl, haloC1-6 alkyl, aryl, heteroaryl, C3-6cycloalkyl, heterocycloalkyl, (aryl)C1-6alkyl, (heteroaryl)C1-6 alkyl, (cycloalkyl)C1-6alkyl, and (heterocycloalkyl)C1-6 alkyl, any of which is optionally substituted with 1 or 2 R8 groups; and
each R8 is independently chosen from C1-6 alkyl, haloC1-6 alkyl, C3-6 cycloalkyl, and haloC3-6 cycloalkyl.

### Claim 12 (depends on 11)

The compound as recited in claim 11, or a salt thereof, wherein A comprises 5 or 6 ring members.

### Claim 13 (depends on 12)

The compound as recited in claim 12, or a salt thereof, wherein each R6 is independently chosen from C1-6 alkyl, haloC1-6alkyl, (C1-6alkoxy)C1-6 alkyl, (haloC1-6 alkoxy)C1-6 alkyl, (C3-6cycloalkyl)C1-6alkyl, (3-6 membered heterocycloalkyl)C1-6alkyl, (aryl)C1-6alkyl, (heteroaryl)C1-6 alkyl, ((C1-6 alkyl)aryl)C1-6 alkyl, and ((C1-6 alkyl)heteroaryl)C1-6alkyl.

### Claim 14 (depends on 13)

The compound as recited in claim 13, or a salt thereof, wherein:
Z is chosen from —CH2—, —C(CH3)2—,
—CF2—, and —O—; and
each Y is —CH2—.

### Claim 15 (depends on 14)

The compound as recited in claim 14, or a salt thereof, wherein Z is chosen from —CH2—, —C(CH3)2—,
—CF2—, and —O—.

### Claim 16 (depends on 15)

The compound as recited in claim 15, or a salt thereof, wherein X1 is N and X2 is C.

### Claim 17 (depends on 16)

The compound as recited in claim 16, or a salt thereof, wherein:
each R3 is independently chosen from cyano, fluoro, hydroxy, C1-6 alkyl, C1-6 fluoroalkyl, and C1-6 hydroxyalkyl, or
any two R3, when directly attached to the same atom, forms a 3-7 membered cycloalkyl ring.

### Claim 18 (depends on 17)

The compound as recited in claim 17, or a salt thereof, wherein R4a and R4b, together with the atom to which they are attached, form a ring chosen from oxetane, tetrahydrofuran, oxane, azetidine, pyrrolidine, and piperidine, any of which is optionally substituted with 1 or 2 R6 groups.

### Claim 19 (depends on 17)

The compound as recited in claim 17, or a salt thereof, wherein R4a and R4b, together with the atom to which they are attached, form a ring chosen from cyclopentane and cyclohexane, either of which is optionally substituted with 1 or 2 R6 groups.

### Claim 20 (depends on 17)

The compound as recited in claim 17, or a salt thereof, wherein R4a and R4b, together with the atom to which they are attached, form a lactam ring, which is optionally substituted with 1 or 2 R6 groups.

### Claim 21 (depends on 1)

The compound as recited in claim 1, having structural Formula IIb:
or a salt thereof, wherein:
A is a monocyclic heterocycloalkyl ring comprising 5 to 7 ring members including:
X1 and X2,
Z, which is chosen from —CH2—, —CHR3—, —C(R3)2—, —N(R5a)—, N(COR5a)—,
N(CONR5aR5b)—, N(SO2R5a)—, —O—, and —SO2—, and all other ring members Y, which are chosen from —CH2—, —CHR2—, and —C(R2)2—;
R1a, R1b, and R1c are independently chosen from H and CH3;
each R2 and R3 is independently chosen from cyano, halo, hydroxy, C1-6alkyl,
C1-6haloalkyl, C1-6hydroxyalkyl, (C1-6alkoxy)C1-6 alkyl; OR5a, C(O)R5a, C(O)OR5a, C(O)NR5aR5b, SO2R5a; SO2NR5aR5b, NR5aR5b, NR5aC(O)R5b, NR5CC(O)OR5b, NR5cC(O)NR5aR5b, and NR5aSO2R5b, or
any two R2 or R3, when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
B is chosen from:
each R4c is independently chosen from —CH2—, —CH(R6d)—, and —C(R6d)2—;
each R5a and R5b is independently chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl, or R5a and R5b, when attached directly to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R5c is chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, (C1-6 alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl;
R6d is chosen from C1-6alkyl, C1-6alkoxy, and (C1-6 alkoxy)C1-6 alkyl;
each R7 is independently chosen from C1-6alkyl, haloC1-6 alkyl, aryl, heteroaryl, C3-6cycloalkyl, heterocycloalkyl, (aryl)C1-6 alkyl, (heteroaryl)C1-6 alkyl, (cycloalkyl)C1-6alkyl, and (heterocycloalkyl)C1-6 alkyl, any of which is optionally substituted with 1 or 2 R8 groups; and
each R8 is independently chosen from C1-6 alkyl, haloC1-6 alkyl, C3-6 cycloalkyl, and haloC3-6 cycloalkyl.

### Claim 22 (depends on 21)

The compound as recited in claim 21, or a salt thereof, wherein B is chosen from:

### Claim 23 (depends on 1)

The compound as recited in claim 1, having structural Formula III:
or a salt thereof, wherein
A is a monocyclic heterocycloalkyl ring comprising 5 or 6 ring members including:
X1 and X2,
Z, which is chosen from —CH2—, —CHR3—, —C(R3)2—, —N(R5a)—, N(COR5a)—,
N(CONR5aR5b)—, N(SO2R5a)—, —O—, and —SO2—, and
all other ring members Y, which are chosen from —CH2—, —CHR2—, and —C(R2)2—;
R1a, R1b, and R1c are independently chosen from H and CH3;
either X1 is C and X2 is N, or X1 is N and X2 is C;
W is C(R6b);
each R2 and R3 is independently chosen from cyano, halo, hydroxy, C1-6alkyl, C1-6haloalkyl, C1-6hydroxyalkyl, (C1-6alkoxy)C1-6 alkyl; OR5a, C(O)R5a, C(O)OR5a, C(O)NR5aR5b, SO2R5a; SO2NR5aR5b, NR5aR5b, NR5aC(O)R5b, NR5cC(O)OR5b, NR5cC(O)NR5aR5b, and NR5aSO2R5b, or
any two R2 or R3, when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
each R5a and R5b is independently chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl, or
R5a and R5b, when attached directly to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R5c is chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, (C1-6alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl;
R6a and R6b are independently chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, (C1-6alkoxy)C1-6 alkyl, (haloC1-6 alkoxy)C1-6 alkyl, C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, (C3-6 alkoxy)C3-6 cycloalkyl, (C3-6 cycloalkyl)C1-6alkyl, (C3-6 heterocycloalkyl)C1-6alkyl, (aryl)C1-6 alkyl, (heteroaryl)C1-6 alkyl, ((C1-6 alkyl)aryl)C1-6 alkyl, ((C1-6alkyl)heteroaryl)C1-6alkyl, OR7, CH2OR7, CH2CH2OR7, COR7, COOH, COOR7, CONH2, CONHR7, CON(R7)2, NHCOR7, NR7COR7, NHCONH2, NHCONHR7, NHCON(R7)2, NR7CONH2, NR7CONHR7, NR7CON(R7)2, SO2R7, SO2NHR7, SO2N(R7)2, NHSO2R7, NR7SO2R7, carboxy, cyano, halo, hydroxy, and oxo;
each R7 is independently chosen from C1-6alkyl, haloC1-6alkyl, aryl, heteroaryl, C3-6cycloalkyl, C3-6 heterocycloalkyl, (aryl)C1-6 alkyl, (heteroaryl)C1-6 alkyl, (cycloalkyl)C1-6alkyl, and (heterocycloalkyl)C1-6alkyl, any of which is optionally substituted with 1 or 2 R8 groups;
each R8 is independently chosen from C1-6alkyl, haloC1-6 alkyl, C3-6 cycloalkyl, and haloC3-6 cycloalkyl; and
p is chosen from 1 and 2.

### Claim 24 (depends on 23)

The compound as recited in claim 23, or a salt thereof, wherein R6a and R6b are independently chosen from H, C1-6alkyl, haloC1-6alkyl, (C1-6alkoxy)C1-6 alkyl, (haloC1-6alkoxy)C1-6alkyl, C3-6 cycloalkyl, (C3-6 alkoxy)C3-6 cycloalkyl, OR7, COR7, COOH, COOR7, CONH2, CONHR7, CON(R7)2, HCOR7, NHCONHR7, NHCON(R7)2, SO2R7, SO2NHR7, SO2N(R7)2, NHSO2R7, cyano, halo, hydroxy, and oxo.

### Claim 25 (depends on 24)

The compound as recited in claim 24, or a salt thereof, wherein:
R6a and R6b are independently chosen from H, C1-6alkyl, haloC1-6alkyl, (C1-6alkoxy)-C1-6alkyl, (haloC1-6alkoxy)C1-6 alkyl, OR7, COR7, COOR7, CONH2, CONHR7, CON(R7)2, SO2R7, SO2NHR7, SO2N(R7)2, NHSO2R7, cyano, halo, hydroxy, and oxo; and
each R7 is independently chosen from C1-6 alkyl, haloC1-6alkyl, C3-6 cycloalkyl, and C3-6heterocycloalkyl.

### Claim 26 (depends on 25)

The compound as recited in claim 25, or a salt thereof, wherein:
Z is chosen from —CH2—, —C(CH3)2—,
—CF2—, and —O—;
p is 2; and
each Y is —CH2—.

### Claim 27 (depends on 26)

The compound as recited in claim 26, or a salt thereof, wherein Z is chosen from —CH2—, —C(CH3)2—,
—CF2—, and —O—.

### Claim 28 (depends on 27)

The compound as recited in claim 27, or a salt thereof, wherein:
each R3 is independently chosen from cyano, fluoro, hydroxy, C1-6 alkyl, C1-6 fluoroalkyl, and C1-6 hydroxyalkyl, or
any two R3, when directly attached to the same atom, forms a 3-7 membered cycloalkyl ring.

### Claim 29 (depends on 28)

The compound as recited in claim 28, or a salt thereof, wherein:
R6a and R6b are independently chosen from H, C1-6alkyl, fluoroC1-6alkyl, (C1-6alkoxy)-C1-6 alkyl, (fluoroC1-6 alkoxy)C1-6 alkyl, C3-6 cycloalkyl, (C3-6 alkoxy)C3-6 cycloalkyl, OR7, COR7, COOH, and COOR7; and
each R7 is independently chosen from C1-6 alkyl and fluoroC1-6 alkyl.

### Claim 30 (depends on 29)

The compound as recited in claim 29, or a salt thereof, wherein R6a and R6b are independently chosen from C1-6 alkyl, fluoroC1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl, (fluoroC1-6 alkoxy)C1-6 alkyl, and OR7.

### Claim 31 (depends on 30)

The compound as recited in claim 30, or a salt thereof, wherein at least one of R6a and R6b is chosen from C1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl, and (fluoroC1-6 alkoxy)C1-6 alkyl.

### Claim 32 (depends on 31)

The compound as recited in claim 31, or a salt thereof, wherein at least one of R6a and R6b is chosen from C1-6alkoxymethyl, C1-6alkoxyethyl, and fluoroC1-6alkoxy-ethyl.

### Claim 33 (depends on 1)

The compound as recited in claim 1, having structural Formula IV:
or a salt thereof, wherein:
A is a monocyclic heterocycloalkyl ring comprising 5 to 7 ring members including:
X1 and X2,
Z, which is chosen from —CH2—, —CHR3—, —C(R3)2—, —N(R5a)—, N(COR5a)—,
N(CONR5aR5b)—, N(SO2R5a)—, —O—, and —SO2—, and
all other ring members Y, which are chosen from —CH2—, —CHR2—, and —C(R2)2—;
R1a, R1b, and R1c are independently chosen from H and CH3;
either X1 is C and X2 is N, or X1 is N and X2 is C;
each R2 and R3 is independently chosen from cyano, halo, hydroxy, C1-6alkyl,
C1-6haloalkyl, C1-6hydroxyalkyl, (C1-6alkoxy)C1-6 alkyl; OR5a, C(O)R5a, C(O)OR5a, C(O)NR5aR5b, SO2R5a; SO2NR5aR5b, NR5aR5b, NR5aC(O)R5b, NR5cC(O)OR5b, NR5cC(O)NR5aR5b, and NR5aSO2R5b, or
any two R2 or R3, when directly attached to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
each R5a and R5b is independently chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, (C1-6alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl, or
R5a and R5b, when attached directly to the same atom, forms a 3-7 membered cycloalkyl or heterocycloalkyl ring;
R5c is chosen from H, C1-6alkyl, cyanoC1-6 alkyl, haloC1-6alkyl, hydroxyC1-6 alkyl, (C1-6 alkoxy)C1-6 alkyl; C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, and (C3-6 alkoxy)C3-6 cycloalkyl;
R6a and R6b are independently chosen from H, C1-6alkyl, cyanoC1-6alkyl, haloC1-6alkyl, hydroxyC1-6 alkyl, (C1-6alkoxy)C1-6 alkyl, (haloC1-6 alkoxy)C1-6 alkyl, C3-6 cycloalkyl, cyanoC3-6 cycloalkyl, haloC3-6 cycloalkyl, hydroxyC3-6 cycloalkyl, (C3-6 alkoxy)-C3-6 cycloalkyl, (C3-6 cycloalkyl)C1-6 alkyl, (3-6 membered heterocycloalkyl)C1-6 alkyl, (aryl)C1-6 alkyl, (heteroaryl)C1-6 alkyl, ((C1-6 alkyl)aryl)C1-6 alkyl, ((C1-6 alkyl)-heteroaryl)C1-6 alkyl, OR7, CH2OR7, CH2CH2OR7, COR7, COOH, COOR7, CONH2, CONHR7, CON(R7)2, NHCOR7, NR7COR7, NHCONH2, NHCONHR7, NHCON(R7)2, NR7CONH2, NR7CONHR7, NR7CON(R7)2, SO2R7, SO2NHR7, SO2N(R7)2, NHSO2R7, NR7SO2R7, carboxy, cyano, halo, hydroxy, and oxo;
each R7 is independently chosen from C1-6 alkyl, haloC1-6 alkyl, aryl, heteroaryl, C3-6cycloalkyl, 3-6 membered heterocycloalkyl, (aryl)C1-6 alkyl, (heteroaryl)C1-6 alkyl, (cycloalkyl)C1-6 alkyl, and (heterocycloalkyl)C1-6 alkyl, any of which is optionally substituted with 1 or 2 R8 groups; and
each R8 is independently chosen from C1-6 alkyl, haloC1-6 alkyl, C3-6 cycloalkyl, and haloC3-6 cycloalkyl.

### Claim 34 (depends on 33)

The compound as recited in claim 33, or a salt thereof, wherein:
each R2 and R3 is independently chosen from cyano, halo, hydroxy, C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, (C1-6alkoxy)C1-6 alkyl, or
any two R2 or R3, when directly attached to the same atom, forms a 3-6 membered cycloalkyl ring; and
R6a and R6b are chosen from H, C1-6alkyl, C1-6alkoxy, (C1-6alkoxy)C1-6alkyl, and (fluoroC1-6 alkoxy)C1-6 alkyl.

### Claim 35

A compound chosen from:

### Claim 36 (depends on 1)

A pharmaceutical composition comprising a compound as recited in claim 1 or a salt thereof, together with a pharmaceutically acceptable carrier.