Immunomodulator compounds

• US 10,639,284 B2
• Filed: 06/26/2017
• Issued: 05/05/2020
• Est. Priority Date: 06/27/2016
• Status: Active Grant

• Current Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Original Assignee: ChemoCentryx, Inc. (Amgen Inc.)
• Inventors: Lange, Christopher, Malathong, Viengkham, McMurtrie, Darren J., Punna, Sreenivas, Singh, Rajinder, Yang, Ju, Zhang, Penglie
• Primary Examiner(s): Morris, Patricia L
• Application Number:
  US15/633,569
• Publication Number:
  US 20180008554A1
• Time in Patent Office: 1,044 Days
• Field of Search: 546335, 514357
• CPC Class Codes: A61K 31/015 carbocyclic
• CPC Class Codes: A61K 31/03 aromatic
• CPC Class Codes: A61K 31/085 having an ether linkage to aromatic ring nuclear carbon
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/36 Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07C 215/12 the nitrogen atom of the amino group being further bound to hydrocarbon groups substituted by hydroxy groups
• CPC Class Codes: C07C 229/22 the carbon skeleton being further substituted by oxygen atoms
• CPC Class Codes: C07C 235/20 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/42 having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 255/54 containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2602/08 the other ring being five-membered, e.g. indane
• CPC Class Codes: C07C 317/22 : with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
• CPC Class Codes: C07C 43/168 : containing six-membered aromatic rings and other rings
• CPC Class Codes: C07D 205/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 211/40 : Oxygen atoms
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 213/61 : Halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/80 : in position 3
• CPC Class Codes: C07D 213/85 : in position 3
• CPC Class Codes: C07D 237/08 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/30 : Halogen atoms or nitro radicals
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 5/025 : Boronic and borinic acid compounds
• CPC Class Codes: C07F 9/58 : Pyridine rings
• CPC Class Codes: 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

Abstract

Compounds are provided that are useful as immunomodulators. The compounds have the following Formula (II):

including stereoisomers and pharmaceutically acceptable salts thereof, wherein R¹, R^2a, R^2b, R^2c, R³, R⁴, R⁵, R^6a, R^6b, m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.

Claims

1. A compound of Formula (II)

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof having the formula (IIa)

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof having the formula (IIb)

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R¹ is phenyl, wherein the phenyl is optionally substituted with 1 to 5 R^x substituents.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl optionally substituted with 1 or 2 R^x wherein each R^x is independently selected from halogen, C_1-8 alkyl, O—

C_1-8 alkyl, O—

C_1-8 haloalkyl, —

NR^aR^b, and CN.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is phenyl optionally substituted with F.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R¹ is selected from the group consisting of:

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R^2b and R^2c are both H and R^2a is selected from the group consisting of halogen, C_1-4 alkyl, C_2-4 alkenyl, C_1-3 haloalkyl, —

CN, —

OMe and OEt.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R^2b and R^2c are both H and R^2a is halogen.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R^2b and R^2c are both H and R^2a is Cl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R⁵ is independently selected from the group consisting of halogen, —

CN, −

R^q, —

NR^rR^g, and —

OR^r, wherein each R^r and R^s is independently selected from hydrogen, C_1-8 alkyl and C_1-8 haloalkyl and each R^q is independently selected from the group consisting of C_1-8 alkyl and C_1-8 haloalkyl.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 0.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R^6a is H.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1 and R^6b is selected from the group consisting of F, C_1-4 alkyl, O—

R^u, C_1-4 haloalkyl and NR^uR^v, wherein each R^u and R^v is independently selected from hydrogen, C_1-8 alkyl, and C_1-8 haloalkyl.

16. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1 and R^6b is F.

17. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein

18. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R⁴ is selected from the group consisting of pyridinyl, and —

O—

C_1-2 alkyl-pyridinyl, wherein the pyridinyl is optionally substituted with 1 to 2 R^z, wherein each R^z is independently selected from the group consisting of halogen, —

CN, —

CO₂Rⁿ, —

RⁿR^p, —

ORⁿ, and piperidinyl optionally substituted with OH.

19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is selected from the group consisting of:

20. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R⁴ is

21. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is NR^gR^h, wherein R^g is selected from the group consisting of H, C_1-8 haloalkyl and C_1-8 alkyl, and wherein R^h is —

C_1-8 alkyl substituted with from 1 to 3 substituents independently selected from OH, COOH, SO₂NH₂, CONH₂, CONOH, COO—

C_1-8 alkyl, and PO₃H₂.

22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is NHR^h, wherein R^h is —

C_1-8 alkyl substituted with from 1 to 2 substituents independently selected from OH, COOH, CONH₂, PO₃H₂.

23. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R³ is selected from the group consisting of:

24. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. The compound of claim 1, selected from the group consisting of

26. The compound of claim 1, selected from the group consisting of

27. The compound of claim 1, having the formula

28. The compound of claim 1, having the formula

29. The compound of claim 1, having the formula

30. The compound of claim 1, having the formula