IMMUNOMODULATOR COMPOUNDS

• US 20180008554A1
• Filed: 06/26/2017
• Published: 01/11/2018
• 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
• Granted Patent: US 10,639,284 B2
• Time in Patent Office: Days
• 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)

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

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

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R³ is —

NR^gR^h.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof wherein R^h combined with the N to which it is attached is a mono-, di- or tri-peptide comprising 1-3 natural amino acids and 0-2 non-natural amino acids, wherein

the non-natural aminoacids have an alpha carbon substituent selected from the group consisting of C_2-4 hydroxyalkyl, C_1-3 alkyl-guanidinyl, and C_1-4 alkly-heteroaryl,

the alpha carbon of each natural or non-natural amino acids are optionally further substituted with a methyl group, and

the terminal moiety of the mono-, di-, or tri-peptide is selected from the group consisting of C(O)OH, C(O)O—

C_1-6 alkyl, and PO₃H₂.

8. The compound of claim 1, wherein each natural amino acid of R^h is independently selected from the group consisting of serine, alanine, glycine, lysine, argining, threonine, phenylalanine, tyrosine, asparatate, asparagine, histidine, and leucine.

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R¹ is selected from the group consisting of phenyl and thienyl, wherein the phenyl and thienyl are optionally substituted with 1 to 5 R^x substituents.

10. 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, and optionally when two R^x substituents are on adjacent atoms, they are combined to form a fused six-membered heterocyclic ring optionally substituted with from 1 to 3 substituents independently selected from oxo, C_1-8 haloalkyl and C_1-8 alkyl.

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

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

14. 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.

15. 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.

16. 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.

17. 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^s, and —

OR^r, wherein each R^r and R⁵ 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.

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

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

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

21. 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.

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

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

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

C_1-4 alkyl, O—

C_1-6 alkyl-CN, phenyl, pyridinyl, —

O—

C_1-2 alkyl-pyridinyl, —

O—

C_1-2 alkyl-pyrimidinyl, —

O—

C_1-2 alkyl-pyridazinyl, and —

O—

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

CN, —

CO₂Rⁿ, —

NRⁿR^p, —

ORⁿ, and piperidinyl optionally substituted with OH.

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

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

28. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of NR^gR^h and C_4-6 heterocyclyl wherein the C_4-6 heterocyclyl is optionally substituted with 1 to 3 R^y, 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, C_5-6 heteroaryl, C_5-6 heterocyclyl and PO₃H₂, wherein the C_5-6 heteroaryl and the C_5-6 heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH)₂, COOH, SO₂NH₂, CONH₂, CONOH, PO₃H₂, COO—

C_1-8alkyl, C_1-4alkyl, C_1-4alkyl-OH, C_1-4alkyl-SO₂NH₂, C_1-4alkyl CONH₂, C_1-4alkyl-CONOH, C_1-4alkyl-PO₃H₂, and C_1-4alkyl-COOH and wherein the C_5-6 heterocyclyl is additionally optionally substituted with oxo.

29. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R³ is selected from the group consisting of azetidinyl, pyrrolidinyl and piperidinyl, wherein the azetidinyl, pyrrolidinyl or piperidinyl is linked through the nitrogen atom and wherein the azetidinyl, pyrrolidinyl or piperidinyl is optionally substituted with 1 to 3 R^y, wherein each R is independently selected from the group consisting of —

CO₂H, CONOH, PO₃H₂, OH, SO₂NH₂, CONH₂, and COO—

C_1-8alkyl.

30. 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, tetrazolyl, tetrazolonyl, and pyrazolyl.

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

32. The compound of claim 5, 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, wherein R^2b and R^2c are both H, R^2a is selected from the group consisting of halogen, C_1-4 alkyl, C_1-3 haloalkyl, —

CN, -OMe and OEt, R^6a is H, m is 0, n is 0, R⁴ is

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

38. A method of modulating an immune response mediated by the PD-1 signaling pathway in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

39. A method of enhancing, stimulating, modulating and/or increasing the immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

40. A method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

41. A method of treating a subject suffering from or susceptible to a disease or disorder mediated by the PD-1 signaling pathway, comprising administering to the subject a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.

2. (canceled)

3. (canceled)

13. (canceled)

24. (canceled)

33. (canceled)

34. (canceled)

36. (canceled)

37. (canceled)

42-45. -45. (canceled)