Somatostatin modulators and uses thereof

• US 9,896,432 B2
• Filed: 07/12/2017
• Issued: 02/20/2018
• 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 M
• Application Number:
  US15/647,758
• Publication Number:
  US 20180016252A1
• Time in Patent Office: 223 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 (AIIb), 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:

R^e is hydrogen, F, Cl, Br, —

CH₃, —

CH₂CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCH₂CH₃, or —

OCF₃;

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

CH₃, —

CH₂CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCH₂CH₃, or —

OCF₃.

3. The compound of claim 2, 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, —

SO₂N(R¹⁵)₂ or; 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).

4. The compound of claim 2, 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, or —

CH₂N(R¹⁵)₂; and

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

CN, or —

O-(unsubstituted or substituted C₁-C₄alkyl).

5. The compound of claim 2, 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.

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

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

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(═

NOH)H, —

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;

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, or 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.

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

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

CH₃, —

CHF, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCF₃, or —

CH₂CH₂OH;

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

CH₃, —

CHF, —

CHF₂, —

CF₃, —

CN, —

OCH₃, or —

OCF₃;

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

CH₃, —

CHF, —

CHF₂, —

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

CN, —

OH, —

OCH₃, —

OCF₃, —

NH₂, —

C(═

O)NH₂, —

CONHCH₃, —

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, 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.

9. The compound of claim 1, 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;

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-C₆alkyl, and unsubstituted or substituted C₁-C₆fluoroalkyl;

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.

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

11. The compound of claim 10, 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;

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.

12. The compound of claim 1, wherein the compound has the following structure of Formula (AVb), or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

13. The compound of claim 12, wherein the compound of Formula (AVb) has the one of the following structures, or a pharmaceutically acceptable salt, solvate, diastereomeric mixture, or individual enantiomers thereof:

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

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

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

R^a is hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, —

OCF₃, —

CH₂OH or —

CH₂CH₂OH;

R^b is 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, or —

CH₂(C═

O)NH₂;

R^e is hydrogen, F, Cl, Br, —

CH₃, —

CH₂F, —

CHF₂, —

CF₃, —

CN, —

OH, —

OCH₃, or —

OCF₃;

R¹ hydrogen;

R²is 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 6-membered heterocyclic ring selected from unsubstituted or substituted piperidinyl, unsubstituted or substituted morpholinyl, unsubstituted or substituted thiomorpholinyl, or unsubstituted or substituted piperazinyl.

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

R^a is hydrogen, F, Cl, —

CH₃, —

CF₃, —

CN, —

OH, —

CH₂OH, —

CH₂CH₂OH, —

OCH₃, or —

OCF₃;

R^b is hydrogen, F, Cl, —

CH₃, —

CF₃, —

CN, —

OH, —

OCH₃, or —

OCF₃;

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

CH₃, —

CF₃, —

CN, —

OH, —

NH₂, —

OCH₃, —

OCF₃, —

—

C(═

O)NH₂, —

C(═

NOH)H , or —

C(═

NOCH₃)H;

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

CH₃, —

CF₃, —

CN, —

OH, —

NH₂, —

OCH₃, —

OCF₃;

R¹ hydrogen;

R² is hydrogen;

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.

18. 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.

19. 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.

20. 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.