Somatostatin modulators and uses thereof

• US 10,351,547 B2
• Filed: 12/20/2017
• Issued: 07/16/2019
• Est. Priority Date: 07/14/2016
• Status: Active Grant

• Current Assignee: Crinetics Pharmaceuticals, Inc.
• Original Assignee: Crinetics Pharmaceuticals, Inc.
• Inventors: Zhao, Jian, Han, Sangdon, Kim, Sun Hee, Wang, Shimiao, Zhu, Yunfei
• Primary Examiner(s): Seaman, D Margaret M
• Application Number:
  US15/849,409
• Publication Number:
  US 20190002431A1
• Time in Patent Office: 573 Days
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/08 for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 498/04 Ortho-condensed systems

Abstract

Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

Claims

1. A compound that has the structure of Formula (A), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R¹ and R² are independently hydrogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆heteroalkyl, unsubstituted or substituted C₁-C₆fluoroalkyl, unsubstituted or substituted C₃-C₆cycloalkyl, or substituted or unsubstituted C₂-C₆heterocycloalkyl;

or R¹ and R² are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted N-containing C₂-C₈heterocycloalkyl;

R⁴ and R⁶ are each independently selected from the group consisting of hydrogen and —

CH₃;

R⁷ is hydrogen, —

CH₃, or —

CH₂CH₃;

or R² and R⁷ are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted N-containing C₂-C₈heterocycloalkyl; and

each R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹³ is independently selected from the group consisting of hydrogen and —

CH₃.

3. The compound of claim 2, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

X is CR^f;

Y is CR^f; and

Z is CR^f;

or X is N;

Y is CR^f; and

Z is CR^f;

or X is CR^f;

Y is N; and

Z is CR^f;

or X is CR^f;

Y is CR^f; and

Z is N;

or X is N;

Y is N; and

Z is CR^f;

or X is CR^f;

Y is N; and

Z is N;

or X is N;

Y is N; and

Z is N;

L¹ is absent, —

CH₂—

, —

CHCH₃—

, or —

CH(CH₂CH₃)—

;

L² is —

CH₂—

or absent; and

L³ is —

CH₂—

, CH₂CH₂—

, or absent.

4. The compound of claim 3, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R^e is hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —

CN, —

OH, or —

OR¹⁴; and

each R^f is independently hydrogen, halogen, C₁-C₄alkyl, C₁-C₄fluoroalkyl, —

CN, —

OH, or —

OR¹⁴.

5. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R^A is an unsubstituted or substituted ring A that is an unsubstituted or substituted phenyl, an unsubstituted or substituted monocyclic 5- or 6-membered heteroaryl containing 1-4 N atoms and 0 or 1 O or S atom, or an unsubstituted or substituted monocyclic 5- or 6-membered heteroaryl containing 0-4 N atoms and 1 O or S atoms; and

R^B is an unsubstituted or substituted ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted monocyclic 5- or 6-membered heteroaryl containing 1-4 N atoms and 0 or 1 O or S atom, or unsubstituted or substituted monocyclic heteroaryl containing 0-4 N atoms and 1 O or S atoms.

6. The compound of claim 4, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R^A is an unsubstituted or substituted ring A that is an unsubstituted or substituted phenyl, unsubstituted or substituted furanyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, or unsubstituted or substituted triazinyl; and

R^B is an unsubstituted or substituted ring B that is an unsubstituted or substituted phenyl, unsubstituted or substituted furanyl, unsubstituted or substituted pyrrolyl, unsubstituted or substituted oxazolyl, unsubstituted or substituted thiazolyl, unsubstituted or substituted imidazolyl, unsubstituted or substituted pyrazolyl, unsubstituted or substituted triazolyl, unsubstituted or substituted tetrazolyl, unsubstituted or substituted isoxazolyl, unsubstituted or substituted isothiazolyl, unsubstituted or substituted oxadiazolyl, unsubstituted or substituted thiadiazolyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyridazinyl, or unsubstituted or substituted triazinyl.

22. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, and at least one pharmaceutically acceptable excipient.

23. A method of modulating somatostatin receptor subtype 2 (SSTR2) activity in a mammal comprising administering a compound of claim 1, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, to the mammal in need thereof.

24. A method of treating acromegaly, a neuroendocrine tumor, pain, or combinations thereof in a mammal comprising administering a compound of claim 1, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, to the mammal in need thereof.

7. A compound that has the following structure, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

8. The compound of claim 7, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R^B is

9. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

each R^a is independently hydrogen, halogen, unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄heteroalkyl, —

CN, —

OH, —

OR¹⁴, —

CO₂R¹⁵, —

CH₂CO₂R¹⁵, —

C(═

O)N(R¹⁵)₂, —

CH₂C(═

O)N(R¹⁵)₂, —

N(R¹⁵)₂, —

CH₂N(R¹⁵)₂, —

CH(CF₃)N(R¹⁵)₂, —

NR¹⁵C(═

O)R¹⁴, —

CH₂NR¹⁵C(═

O)R¹⁴, —

SR¹⁴, —

S(═

O)R¹⁴, —

SO₂R¹⁴, or —

SO₂N(R¹⁵)₂; and

each R^b is independently hydrogen, halogen, unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄heteroalkyl, —

CN, —

OH, or —

O-(unsubstituted or substituted C₁-C₄alkyl).

10. The compound claim 8, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

each R^a is independently hydrogen, halogen, unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄heteroalkyl, —

CN, —

OH, —

OR¹⁴, —

CO₂R¹⁵, —

CH₂CO₂R¹⁵, —

C(═

O)N(R¹⁵)₂, —

CH₂C(═

O)N(R¹⁵)₂, —

N(R¹⁵)₂, —

CH₂N(R¹⁵)₂, —

CH(CF₃)N(R¹⁵)₂, —

NR¹⁵C(═

O)R¹⁴, or —

CH₂NR¹⁵C(═

O)R¹⁴;

each R^b is independently hydrogen, halogen, unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄fluoroalkyl, unsubstituted or substituted C₁-C₄heteroalkyl, —

CN, —

OH, or —

O-(unsubstituted or substituted C₁-C₄alkyl);

each R^c is independently hydrogen, halogen, unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄fluoroalkyl, —

CN, —

OH, —

OR¹⁴, —

CO₂R¹⁵, —

CH₂CO₂R¹⁵, —

C(═

O)N(R¹⁵)₂, —

NR¹⁵C(═

O)NR¹⁵OR¹⁴, —

C(═

O)NR¹⁵OR¹⁵, —

CH₂C(═

O)N(R¹⁵)₂, —

N(R¹⁵)₂, —

CH₂N(R¹⁵)₂, —

CH(CF₃)N(R¹⁵)₂, —

NR¹⁵C(═

O)R¹⁴, —

CH₂NR¹⁵C(═

O)R¹⁴, —

SR¹⁴, —

S(═

O)R¹⁴, —

SO₂R¹⁴, —

SO₂N(R¹⁵)₂, or N(R¹⁵)SO₂R¹⁴; and

R^d is independently hydrogen, halogen, unsubstituted or substituted C₁-C₄alkyl, unsubstituted or substituted C₁-C₄fluoroalkyl, unsubstituted or substituted monocyclic 4-7-membered heterocycle, —

CN, —

OH, —

O-(unsubstituted or substituted C₁-C₄alkyl), —

O-(unsubstituted or substituted C₁-C₄heteroalkyl), —

C(═

O)R¹⁵, —

OC(═

O)R¹⁵, —

CO₂R¹⁵, —

CH₂CO₂R¹⁵, —

C(═

O)N(R¹⁵)₂, —

OC(═

O)N(R¹⁵)₂, —

NR¹⁵C(═

O)N(R¹⁵)₂, —

NR¹⁵C(═

O)OR¹⁴, —

NR¹⁵C(═

O)NR¹⁵OR¹⁴, —

C(═

O)NR¹⁵OR¹⁵, —

CH₂C(═

O)N(R¹⁵)₂, —

N(R¹⁵)₂, —

CH₂N(R¹⁵)₂, —

CH(CF₃)N(R¹⁵)₂, —

NR¹⁵C(═

O)R¹⁴, —

CH₂NR¹⁵C(═

O)R¹⁴, —

SO₂N(R¹⁵)₂, —

C(═

NOR¹⁵)R¹⁵, —

N(R¹⁵)SO₂R¹⁴, —

C(═

O)NR¹⁵S(═

O)₂R¹⁴, —

S(═

O)₂NR¹⁵C(═

O)R¹⁴, or —

C(═

NR¹⁵)N(R¹⁵)₂;

or if one R^c and one R^d are on adjacent atoms of ring B then the adjacent R^c and R^d groups are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic carbocycle or an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle.

11. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

each R^a is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH₂CH₂CH₂CH₃, —

CH₂CH(CH₃)₂, —

CH(CH₃)(CH₂CH₃), —

C(CH₃)₃, —

CH₂OH, —

CH₂CN, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCH₂CH₃, —

OCF₃, —

CH₂CH₂OH, —

CO₂H, —

CO₂CH₃, —

CO₂CH₂CH₃, —

CH₂CO₂H, —

CH₂CO₂CH₃, —

CH₂CO₂CH₂CH₃, —

C(═

O)NH₂, —

C(═

O)NHCH₃, —

C(═

O)N(CH₃)₂, —

CH₂C(═

O)NH₂, —

CH₂C(═

O)NHCH₃, —

CH₂C(═

O)N(CH₃)₂, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

CH₂NH₂, —

CH₂NHCH₃, or —

CH₂N(CH₃)₂;

each R^b is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH₂CH₂CH₂CH₃, —

CH₂CH(CH₃)₂, —

CH(CH₃)(CH₂CH₃), —

C(CH₃)₃, —

CH₂OH, —

CH₂CN, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCH₂CH₃, or —

OCF₃;

each R^c is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH₂CH₂CH₂CH₃, —

CH₂CH(CH₃)₂, —

CH(CH₃)(CH₂CH₃), —

C(CH₃)₃, —

CH₂OH, —

CH₂CN, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCH₂CH₃, —

OCF₃, —

CO₂H, —

CO₂CH₃, —

CO₂CH₂CH₃, —

CH₂CO₂H, —

CH₂CO₂CH₃, —

CH₂CO₂CH₂CH₃, —

C(═

O)NH₂, —

C(═

O)NHCH₃, —

C(═

O)NHOCH₃, —

C(═

O)N(CH₃)₂, —

SO₂N(CH₃)₂, —

C(═

NOCH₃)H, —

CH₂C(═

O)NH₂, —

CH₂C(═

O)NHCH₃, —

CH₂C(═

O)N(CH₃)₂, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

NHCO₂CH₃, —

NHSO₂CH₃, —

CH₂NH₂, —

CH₂NHCH₃, —

CH₂N(CH₃)₂, CH(CF₃)NH₂, azetidinyl, or pyrrolidinyl; and

each R^d is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂CH₃, —

CH₂CH₂CH₃, —

CH(CH₃)₂, —

CH₂CH₂CH₂CH₃, —

CH₂CH(CH₃)₂, —

CH(CH₃)(CH₂CH₃), —

C(CH₃)₃, —

CH₂OH, —

CH₂CN, —

CH₂F, —

CHF₂, —

CF₃, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, —

CN, —

OH, —

OCH₃, —

OCH₂CH₃, —

OCF₃, —

OCH₂OCH₃, —

OCH₂OCH₂CH₃, —

OCH₂CH₂OH, —

C(═

O)NHOCH₃, —

C(═

NOH)H, —

C(═

NOCH₃)H, —

CH₂C(═

O)NH₂, —

NH₂, NHCO₂CH₃, NHSO₂CH₃, NH(C═

O)NHCH₃, NH(C═

O)NHOCH₃, CH(CF₃)NH₂;

or if one R^c and one R^d are on adjacent atoms of ring B then the adjacent R^c and R^d groups are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5- or 6-membered monocyclic heterocycle.

12. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

each R^a is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCF₃, —

CH₂OH or —

CH₂CH₂OH;

each R^b is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCF₃;

each R^c is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, —

CN, —

OH, —

OCH₃, —

OCF₃, —

NH₂, —

C(═

O)NH₂, —

C(═

NOH)H, —

C(═

NOCH₃)H, —

SO₂CH₃, —

SO₂N(CH₃)₂, azetidinyl, or pyrrolidinyl; and

each R^d is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCF₃, —

OCH₂OCH₃, —

CH₂OH, —

OCH₂CH₂OH, —

C(═

O)NH₂, —

C(═

O)NHOCH₃, NH₂, —

NHCO₂CH₃, —

NH(C═

O)NHOCH₃, or —

CH₂(C═

O)NH₂;

or if one R^c and one R^d are on adjacent atoms of ring B then the adjacent R^c and R^d groups are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 5-membered monocyclic heterocycle.

13. The compound of claim 8, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

X is CR^f;

Y is CR^f; and

Z is CR^f;

or X is N;

Y is CR^f; and

Z is CR^f;

or X is CR^f;

Y is N; and

Z is CR^f;

or X is CR^f;

Y is CR^f; and

Z is N;

or X is N;

Y is N; and

Z is CR^f;

or X is CR^f;

Y is N; and

Z is N;

or X is N;

Y is N; and

Z is N;

L¹ is absent, —

CH₂—

, —

CH(CH₃)—

, or —

CH(CH₂CH₃)—

; and

L² is —

CH₂—

; and

L³ is —

CH₂—

;

or L² is absent; and

L³ is —

CH₂CH₂—

;

or L² is absent; and

L³ is absent;

or L² is absent; and

L³ is —

CH₂—

.

14. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R¹ hydrogen;

R² is hydrogen, unsubstituted or substituted C₁-C₆alkyl, unsubstituted or substituted C₁-C₆fluoroalkyl, unsubstituted or substituted C₃-C₆cycloalkyl, or substituted or unsubstituted C₂-C₆heterocycloalkyl;

or R¹ and R² are taken together with the nitrogen atom to which they are attached to form ring C that is an unsubstituted or substituted N-containing C₂-C₆heterocycloalkyl;

R³ is hydrogen;

R⁵ is selected from the group consisting of hydrogen, halogen, —

OH, —

OR¹⁴, —

S(═

O)₂R¹⁴, —

N(R¹⁵)₂, —

CN, —

C(═

O)OR¹⁵, —

C(═

O)N(R¹⁵)₂, unsubstituted or substituted C₁-C₆ alkyl, and unsubstituted or substituted C₁-C₆fluoroalkyl;

or R³ and R⁵ are taken together to form a bond, —

CH₂—

, or —

CH₂CH₂—

;

or R² and R⁵ are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 7-membered saturated N-containing heterocyclic ring; and

R⁷ is hydrogen or C₁-C₄alkyl;

or R² and R⁷ are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted 4- to 7-membered N-containing heterocycloalkyl.

15. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R¹ hydrogen;

R² is hydrogen, —

CH₃, —

CH₂CH₃, —

CH₂CH₂OH, —

CH₂CH₂OCH₃, —

CH₂CH₂F, —

CH₂CH₂NH₂, —

CH₂CH₂NHCH₃, —

CH₂CH₂N(CH₃)₂, —

CH₂CH₂CH₃, —

CH(CH₃)₂, cyclopropyl, —

CH₂CH₂CH₂F, —

CH₂CH₂CH₂OH, —

CH₂CH₂CH₂OCH₃, —

CH₂CH₂CH₂CH₃, —

CH₂CH(CH₃)₂, —

CH(CH₃)(CH₂CH₃), —

C(CH₃)₃, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl;

or R¹ and R² are taken together with the nitrogen atom to which they are attached to form ring C that is an unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl;

R³ is hydrogen;

R⁵ is hydrogen, F, Cl, Br, —

OH, —

OCH₃, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

OCH₂CH₃, —

OCF₃, —

CH₃, —

CH₂CH₃, —

CH₂F, —

CHF₂, —

CF₃—

CN, —

C(═

O)OCH₃, —

C(═

O)NH₂, —

C(═

O)NHCH₃, or —

C(═

O)N(CH₃)₂;

or R² and R⁵ are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl; and

R⁷ is hydrogen, —

CH₃, or —

CH₂CH₃;

or R² and R⁷ are taken together with the nitrogen atom to which they are attached to form an unsubstituted or substituted monocyclic 4- to 7-membered heterocyclic ring selected from unsubstituted or substituted azetidinyl, unsubstituted or substituted pyrrolidinyl, unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, unsubstituted or substituted piperazinyl, or unsubstituted or substituted azepanyl.

16. The compound of claim 13, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

17. The compound of claim 13, wherein the compound has the following structure, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

18. The compound of claim 17, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R¹ is hydrogen; and

R² is hydrogen, methyl, ethyl, 2-fluoroethyl, 2-hydroxyethyl, 2-methoxyethyl, n-propyl, i-propyl, cyclopropyl, 3-fluoropropyl, 3-methoxypropyl, n-butyl, i-butyl, sec-butyl, cyclobutyl, or tert-butyl, or oxetanyl.

19. The compound of claim 17, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R¹ is hydrogen; and

R² is hydrogen.

20. The compound of claim 17, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

each R^a is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCF₃, —

CH₂OH or —

CH₂CH₂OH;

each R^b is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, or —

OCF₃;

each R^c is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, —

CN, —

OH, —

OCH₃, —

OCF₃, —

NH₂, —

C(═

O)NH₂, —

C(═

NOH)H, —

C(═

NOCH₃)H, —

SO₂CH₃, —

SO₂N(CH₃)₂, azetidinyl, or pyrrolidinyl;

each R^d is independently hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCF₃, —

OCH₂OCH₃, —

CH₂OH, —

OCH₂CH₂OH, —

C(═

O)NH₂, —

C(═

O)NHOCH₃, —

NH₂, —

NHCO₂CH₃, —

NH(C═

O)NHOCH₃, —

CH₂(C═

O)NH₂;

R^e is hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, or —

OCF₃;

R¹ hydrogen;

R² is hydrogen; and

R⁵ is hydrogen, F, Cl, Br, —

OH, —

OCH₃, —

NH₂, —

NHCH₃, —

N(CH₃)₂, —

OCH₂CH₃, —

OCF₃, —

CH₃, —

CH₂CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

C(═

O)OCH₃, —

C(═

O)NH₂, —

C(═

O)NHCH₃, or —

C(═

O)N(CH₃)₂;

or R² and R⁵ are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted monocyclic 6-membered heterocyclic ring selected from unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl.

21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof, wherein:

R^a is independently hydrogen, F, Cl, —

CH₃, —

CF₃, —

CN, —

OH, —

CH₂OH, —

CH₂CH₂OH, —

OCH₃, or —

OCF₃,

R^b is independently hydrogen, F, Cl, —

CH₃, —

CF₃, —

CN, —

OH, —

OCH₃, or —

OCF₃;

each R^c is independently hydrogen, F, Cl, —

CH₃, —

CF₃, —

CN, —

OH, —

OCH₃, —

NH₂, —

C(═

O)NH₂, —

C(═

NOH)H, or —

C(═

NOCH₃)H;

each R^d is independently hydrogen, F, Cl, —

CH₃, —

CF₃, —

CN, —

OH, —

NH₂, —

OCH₃, or —

OCF₃;

X is CR^f;

Y is CR^f; and

Z is CR^f;

or X is N;

Y is CR^f; and

Z is CR^f;

or X is CR^f;

Y is N; and

Z is CR^f;

or X is CR^f;

Y is CR^f; and

Z is N;

R¹ hydrogen;

R² is hydrogen; and

R⁵ is hydrogen;

or R² and R⁵ are taken together with the intervening atoms to which they are attached to form an unsubstituted or substituted morpholinyl.