# US 11,993,574 B2 · Pyrazole and imidazole compounds for inhibition of IL-17 and RORgamma

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- Number: US 11,993,574 B2
- Document ID: US11993574B2
- Status: Granted
- Kind: B2
- Application number: 17/251,295
- Filed: 2019-06-17
- Published: 2021-09-23
- Granted: 2024-05-28
- Earliest claimed: 2018-06-15
- Assignees: Reata Pharmaceuticals, Inc.
- Applicants: Reata Pharmaceuticals, Inc.
- Inventors: Xin Jiang; Melean Visnick; Christopher F. Bender; Gary Bolton; Bradley Caprathe; Chitase Lee; Brian Kornberg; Patrick O'Brien; Martha R. Hotema
- Web page: https://patentgrep.com/patent/US11993574B2

## CPC

- C07D 231/54: condensed with carbocyclic rings or ring systems
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07D 235/02: condensed with carbocyclic rings or ring systems
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 417/14: containing three or more hetero rings
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are compounds of the formula: as well as analogs thereof, wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used to modulate the activity of IL-17 and RORγ. Also provided are methods of administering compounds and composition provided herein to a patient in need thereof, for example, for the treatment or prevention of diseases or disorders associated with inflammation or for autoimmune disorders.

## Claims

### Claim 1

A compound of the formula:
wherein:
n is 0, 1, or 2;
R1 is cyano, fluoro, —CF3, or —C(O)Ra, wherein:
Ra is hydroxy or amino; or
alkoxy(C≤6), alkylamino(C≤6), dialkylamino(C≤6), or a substituted version of any of these groups;
R2 is hydrogen; or
alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R3 is alkyl(C≤12), alkenyl(C≤12), aryl(C≤12), aralkyl(C≤12), or a substituted version of any of these groups;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3;
R6 is absent or amino; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1 further defined as:
wherein:
n is 0, 1, or 2;
R1 is cyano, fluoro, —CF3, or —C(O)Ra, wherein:
Ra is hydroxy or amino; or
alkoxy(C≤6), alkylamino(C≤6), dialkylamino(C≤6), or a substituted version of any of these groups;
R2 is hydrogen; or
alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R3 is alkyl(C≤12), alkenyl(C≤12), aryl(C≤12), aralkyl(C≤12), or a substituted version of any of these groups;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3;
R6 is absent or amino; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, further defined as:
wherein:
R2 independently is hydrogen; or
alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3;
R6 is absent or amino; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, further defined as:
wherein:
R2 independently is hydrogen; or
alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3; and
R6 is absent; or
alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkane-diyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocyclo-alkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, further defined as:
wherein:
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3; and
R6 is absent; or
alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkane-diyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocyclo-alkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R3 is alkyl(C≤12) or substituted alkyl(C≤12) or R1 is cyano.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R2 is hydrogen, alkyl(C≤12), or substituted alkyl(C≤12).

### Claim 8 (depends on 1)

The compound of claim 1, wherein R4 is aryl(C≤12), substituted aryl(C≤12), -arenediyl(C≤12)-aryl(C≤12), or substituted -arenediyl(C≤12)-aryl(C≤12).

### Claim 9 (depends on 1)

The compound of claim 1, wherein R4 is -arenediyl(C≤12)-heterocycloalkyl(C≤12) or substituted -arenediyl(C≤12)-heterocycloalkyl(C≤12).

### Claim 10 (depends on 1)

The compound of claim 1, wherein R4 is heteroaryl(C≤12), substituted heteroaryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), substituted -arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), substituted -heteroarenediyl(C≤12)-aryl(C≤12), -heteroarenediyl(C≤12)-heteroaryl(C≤12), or substituted -heteroarenediyl(C≤12)-heteroaryl(C≤12).

### Claim 11 (depends on 1)

The compound of claim 1, wherein R5 is aryl(C≤12), substituted aryl(C≤12), -arenediyl(C≤12)-aryl(C≤12), or substituted -arenediyl(C≤12)-aryl(C≤12).

### Claim 12 (depends on 1)

The compound of claim 1, wherein R5 is -arenediyl(C≤12)-heterocycloalkyl(C≤12) or substituted -arenediyl(C≤12)-heterocycloalkyl(C≤12).

### Claim 13 (depends on 1)

The compound of claim 1, wherein R5 is heteroaryl(C≤12), substituted heteroaryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), substituted -arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), substituted -heteroarenediyl(C≤12)-aryl(C≤12), -heteroarenediyl(C≤12)-heteroaryl(C≤12), or substituted -heteroarenediyl(C≤12)-heteroaryl(C≤12).

### Claim 14 (depends on 1)

The compound of claim 1, wherein R5 is -heteroarenediyl(C≤12)-heterocycloalkyl(C≤12) or substituted -heteroarenediyl(C≤12)-heterocycloalkyl(C≤12).

### Claim 15 (depends on 1)

The compound of claim 1, wherein R6 is aryl(C≤18), substituted aryl(C≤18), heteroaryl(C≤18), or substituted heteroaryl(C≤18).

### Claim 16 (depends on 1)

The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt of any of the above formulas.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising:
(a) a compound of claim 1; and
(b) an excipient.

### Claim 18 (depends on 1)

The compound of claim 1, wherein R6 is cycloalkyl(C≤12), substituted cycloalkyl(C≤12), heterocycloalkyl(C≤12), or substituted heterocycloalkyl(C≤12).

### Claim 19

A compound of the formula:
wherein:
n is 0, 1, or 2;
R1 is cyano, fluoro, —CF3, or —C(O)Ra, wherein:
Ra is hydroxy or amino; or
alkoxy(C≤6), alkylamino(C≤6), dialkylamino(C≤6), or a substituted version of any of these groups;
R2 is hydrogen; or
alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R3 is alkyl(C≤12), alkenyl(C≤12), aryl(C≤12), aralkyl(C≤12), or a substituted version of any of these groups;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3;
R6 is absent or amino; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The compound of claim 19 further defined as:
wherein:
n is 0, 1, or 2;
R1 is cyano, fluoro, —CF3, or —C(O)Ra, wherein:
Ra is hydroxy or amino; or
alkoxy(C≤6), alkylamino(C≤6), dialkylamino(C≤6), or a substituted version of any of these groups;
R2 is hydrogen; or
alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R3 is alkyl(C≤12), alkenyl(C≤12), aryl(C≤12), aralkyl(C≤12), or a substituted version of any of these groups;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3;
R6 is absent or amino; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 19)

The compound of claim 19, further defined as:
wherein:
R2 is hydrogen; or
cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3;
R6 is absent or amino; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 19)

The compound of claim 19, further defined as:
wherein:
R2 is hydrogen; or
alkyl(C≤12), cycloalkyl(C≤12), alkenyl(C≤12), alkynyl(C≤12), aryl(C≤18), aralkyl(C≤18), heteroaryl(C≤18), heteroaralkyl(C≤18), or a substituted version of any of these groups;
R2′ is hydrogen;
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3; and
R6 is absent; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 19)

The compound of claim 19, further defined as:
wherein:
R4 and R5 are each independently absent; or
cycloalkyl(C≤12), heterocycloalkyl(C≤12), aryl(C≤12), aralkyl(C≤12), heteroaryl(C≤12), heteroaralkyl(C≤12), -arenediyl(C≤12)-alkyl(C≤12), -arenediyl(C≤12)-aryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), -arenediyl(C≤12)-heterocycloalkyl(C≤12), -arenediyl(C≤12)-cyclo-alkyl(C≤12), -heteroarenediyl(C≤12)-alkyl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), -hetero-arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-hetero-cycloalkyl(C≤12), -heteroarenediyl(C≤12)-cycloalkyl(C≤12), -heterocycloalkanediyl(C≤12)-aryl(C≤12), -heterocycloalkanediyl(C≤12)-heteroaryl(C≤12), or a substituted version of any of these groups; or
a group of the formula:
wherein 1 and m are each 0, 1, 2, or 3; and
R6 is absent; or
alkylamino(C≤12), dialkylamino(C≤12), cycloalkylamino(C≤12), dicycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), arylamino(C≤12), diarylamino(C≤12), alkyl(C≤12), cycloalkyl(C≤12), -alkanediyl(C≤12)-cycloalkyl(C≤12), -alkanediyl(C≤18)-aralkoxy(C≤18), heterocycloalkyl(C≤12), aryl(C≤18), -arenediyl(C≤12)-alkyl(C≤12), aralkyl(C≤18), -arenediyl(C≤18)-heterocycloalkyl(C≤12), heteroaryl(C≤18), -heteroarenediyl(C≤12)-alkyl(C≤12), heteroaralkyl(C≤18), acyl(C≤12), alkoxy(C≤12), or a substituted version of any of these groups;
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 19)

The compound of claim 19, wherein R3 is alkyl(C≤12) or substituted alkyl(C≤12) or R1 is cyano.

### Claim 25 (depends on 19)

The compound of claim 19, wherein R2 is hydrogen, alkyl(C≤12), or substituted alkyl(C≤12).

### Claim 26 (depends on 19)

The compound of claim 19, wherein R4 is aryl(C≤12), substituted aryl(C≤12), -arenediyl(C≤12)-aryl(C≤12), or substituted -arenediyl(C≤12)-aryl(C≤12).

### Claim 27 (depends on 19)

The compound of claim 19, wherein R4 is -arenediyl(C≤12)-heterocycloalkyl(C≤12) or substituted -arenediyl(C≤12)-heterocycloalkyl(C≤12).

### Claim 28 (depends on 19)

The compound of claim 19, wherein R4 is heteroaryl(C≤12), substituted heteroaryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), substituted -arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), substituted -heteroarenediyl(C≤12)-aryl(C≤12), -heteroarenediyl(C≤12)-heteroaryl(C≤12), or substituted -heteroarenediyl(C≤12)-heteroaryl(C≤12).

### Claim 29 (depends on 19)

The compound of claim 19, wherein R5 is aryl(C≤12), substituted aryl(C≤12), -arenediyl(C≤12)-aryl(C≤12), or substituted -arenediyl(C≤12)-aryl(C≤12).

### Claim 30 (depends on 19)

The compound of claim 19, wherein R5 is -arenediyl(C≤12)-heterocycloalkyl(C≤12) or substituted -arenediyl(C≤12)-heterocycloalkyl(C≤12).

### Claim 31 (depends on 19)

The compound of claim 19, wherein R5 is heteroaryl(C≤12), substituted heteroaryl(C≤12), -arenediyl(C≤12)-heteroaryl(C≤12), substituted -arenediyl(C≤12)-heteroaryl(C≤12), -heteroarenediyl(C≤12)-aryl(C≤12), substituted -heteroarenediyl(C≤12)-aryl(C≤12), -heteroarenediyl(C≤12)-heteroaryl(C≤12), or substituted -heteroarenediyl(C≤12)-heteroaryl(C≤12).

### Claim 32 (depends on 19)

The compound of claim 19, wherein R5 is -heteroarenediyl(C≤12)-heterocycloalkyl(C≤12) or substituted -heteroarenediyl(C≤12)-heterocycloalkyl(C≤12).

### Claim 33 (depends on 19)

The compound of claim 19, wherein R6 is aryl(C≤18), substituted aryl(C≤18), heteroaryl(C≤18), or substituted heteroaryl(C≤18).

### Claim 34 (depends on 19)

The compound of claim 19, wherein R6 is cycloalkyl(C≤12), substituted cycloalkyl(C≤12), heterocycloalkyl(C≤12), or substituted heterocycloalkyl(C≤12).

### Claim 35 (depends on 19)

The compound of claim 19, wherein R6 is alkylamino(C≤12), substituted alkylamino(C≤12), cycloalkylamino(C≤12), substituted cycloalkylamino(C≤12), alkyl(cycloalkyl)amino(C≤12), or substituted alkyl(cycloalkyl)amino(C≤12).

### Claim 36 (depends on 19)

The compound of claim 19 further defined as:
or a pharmaceutically acceptable salt of any of the above formulas.

### Claim 37 (depends on 19)

A pharmaceutical composition comprising:
(a) a compound of claim 19; and
(b) an excipient.