Diaryl substituted 5,5-fused ring compounds as C5aR inhibitors
The present disclosure provides, inter alia, Compounds of Formula (I) or pharmaceutically acceptable salts thereof that are modulators of the C5a receptor. Also provided are pharmaceutical compositions and methods of use including the treatment of diseases or disorders involving pathologic activation from C5a and non-pharmaceutical applications.
1. A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein,
ring vertex a is N or C(R 2c ), ring vertex b is N or C(R 2d ), and ring vertex e is N or C(R 2e ), wherein no more than one of a, b and e is N;
X 1 is selected from the group consisting of a bond, C 1-8 alkylene, C(O), C(O)—C 1-4 alkylene, and S(O) 2 ;
R 1 is selected from the group consisting of
a) 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S;
b) C 6-10 aryl;
c) C 3-8 cycloalkyl;
d) 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and
e) C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl;
wherein the group —X 1 —R 1 is optionally substituted with 1 to 5 R x substituents;
R 2a and R 2e are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, CN, and halogen, and at least one of R 2a and R 2e is other than hydrogen;
R 2b , R 2c , and R 2d are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, cyano, and halogen;
each R 3 is independently selected from the group consisting of hydroxyl, C 1-4 alkyl, C 1-4 haloalkyl and C 1-4 hydroxyalkyl, and optionally two R 3 groups on the same carbon atom are combined to form oxo (═O), and optionally two R 3 groups and the carbon atoms they are attached to form a 3-6 membered ring with 0-2 hetereoatoms as ring members selected from O, N, and S;
R 4 is independently selected from the group consisting of
each R 5 is independently selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 1-8 haloalkoxy, C 1-8 hydroxyalkyl, halogen, OH, CN, C(O)R 5a and CO 2 R 5a ; wherein each R 5a is independently selected from the group consisting of hydrogen, C 1-4 alkyl, and C 1-4 haloalkyl;
each R x is independently selected from the group consisting of halogen, CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 1-4 hydroxy, C 2-4 alkenyl, C 3-6 cycloalkyl, CO 2 —C 1-4 alkyl, and CONH 2 ;
the subscript m is 0, 1, 2, 3 or 4; and
the subscript n is 0, 1, 2 or 3.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is a bond.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C(O).
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C 1-8 alkylene.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is C(O)—C 1-4 alkylene or S(O) 2 .
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5- to 10-membered heteroaryl having from 1 to 4 heteroatoms as ring vertices selected from N, O and S; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
9. The compound of claim 8 , wherein R 1 is selected from the group consisting of pyrazolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, thiadiazolyl and pyrazinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having formula (Ia) or (Ib):
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6-10 aryl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
12. The compound of claim 11 , wherein R 1 is phenyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-8 cycloalkyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
14. The compound of claim 13 , wherein R 1 is selected from the group consisting of cyclobutyl, cyclopentyl and cyclohexyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is a 4- to 8-membered heterocycloalkyl having from 1 to 2 heteroatoms as ring vertices selected from N, O and S; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
16. The compound of claim 15 , wherein R 1 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl and morpholinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, —C(O)NR 1a R 1b , and —CO 2 R 1a ; wherein R 1a and R 1b are each independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 6-10 aryl, and —C 1-6 alkylene-C 6-10 aryl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, and pyrazinyl; and wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, —O—C 1-6 haloalkyl, —S—C 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-S—C 1-6 alkyl, CN, and halogen.
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R 5 , when present, is independently selected from the group consisting of F, Cl, CN, C 1-4 alkyl and C 1-4 alkoxy.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0, 1 or 2 and each R 5 , when present, is independently selected from the group consisting of F, Cl, CN, CH 3 and OCH 3 .
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2 and each R 3 , when present, is C 1-4 alkyl.
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of phenyl or pyridyl, wherein the group —X 1 —R 1 is optionally substituted with 1 to 4 R x substituents; ring vertices a and b are CH; R 2b is H; ring vertex e is C(R 2e ), and R 2a and R 2e are independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy and halogen; m is 0, 1 or 2 and each R 3 , when present, is CH 3 ; R 4 is selected from the group consisting of
n is 0, 1 or 2 and each R 5 , when present, is selected from the group consisting of F, Cl, CN, CH 3 and OCH 3 .
25. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein —X 1 —R 1 is selected from the group consisting of:
26. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
is selected from the group consisting of
27. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0.
28. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein m is 2 and the two R 3 groups are on the same carbon atom and are combined to form oxo (═O).
29. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said compound is selected from the group consisting of:
30. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
31. The pharmaceutical composition of claim 30 , formulated for oral, intravenous, transdermal or subcutaneous administration.
32. The pharmaceutical composition of claim 30 , further comprising one or more additional therapeutic agents.
33. The pharmaceutical composition of claim 32 , wherein the one or more additional therapeutic agent is selected from the group consisting of corticosteroids, steroids, immunosuppressants, Immunoglobulin G agonists, Dipeptidyl peptidase IV inhibitors, Lymphocyte function antigen-3 receptor antagonists, Interleukin-2 ligands, Interleukin-1 beta ligand inhibitors, IL-2 receptor alpha subunit inhibitors, HGF gene stimulators, IL-6 antagonists, IL-5 antagonists, Alpha 1 antitrypsin stimulators, Cannabinoid receptor antagonists, Histone deacetylase inhibitors, AKT protein kinase inhibitors, CD20 inhibitors, Abl tyrosine kinase inhibitors, JAK tyrosine kinase inhibitors, TNF alpha ligand inhibitors, Hemoglobin modulators, TNF antagonists, proteasome inhibitors, CD3 modulators, Hsp 70 family inhibitors, Immunoglobulin agonists, CD30 antagonists, tubulin antagonists, Sphingosine-1-phosphate receptor-1 agonists, connective tissue growth factor ligand inhibitors, caspase inhibitors, adrenocorticotrophic hormone ligands, Btk tyrosine kinase inhibitors, Complement C1s subcomponent inhibitors, Erythropoietin receptor agonists, B-lymphocyte stimulator ligand inhibitors, Cyclin-dependent kinase-2 inhibitors, P-selectin glycoprotein ligand-1 stimulators, mTOR inhibitors, Elongation factor 2 inhibitors, Cell adhesion molecule inhibitors, Factor XIII agonists, Calcineurin inhibitors, Immunoglobulin G1 agonists, Inosine monophosphate dehydrogenase inhibitors, Complement C1s subcomponent inhibitors, Thymidine kinase modulators, Cytotoxic T-lymphocyte protein-4 modulators, Angiotensin II receptor antagonists, Angiotensin II receptor modulators, TNF superfamily receptor 12A antagonists, CD52 antagonists, Adenosine deaminase inhibitors, T-cell differentiation antigen CD6 inhibitors, FGF-7 ligands, dihydroorotate dehydrogenase inhibitors, Syk tyrosine kinase inhibitors, Interferon type I receptor antagonists, Interferon alpha ligand inhibitors, Macrophage migration inhibitory factor inhibitors, Integrin alpha-V/beta-6 antagonists, Cysteine protease stimulators, p38 MAP kinase inhibitors, TP53 gene inhibitors, Shiga like toxin I inhibitors, Fucosyltransferase 6 stimulators, Interleukin 22 ligands, IRS1 gene inhibitors, Protein kinase C stimulators, Protein kinase C alpha inhibitors, CD74 antagonists, Immunoglobulin gamma Fc receptor IIB antagonists, T-cell antigen CD7 inhibitors, CD95 antagonists, N acetylmannosamine kinase stimulators, Cardiotrophin-1 ligands, Leukocyte elastase inhibitors, CD40 ligand receptor antagonists, CD40 ligand modulators, IL-17 antagonists, TLR-2 antagonists, Mannan-binding lectin serine protease-2 (MASP-2) inhibitors, Factor B inhibitors, Factor D inhibitors, C3aR modulators, C5aR2 modulators, T cell receptor antagonists, PD-1 inhibitors, PD-L1 inhibitors, TIGIT inhibitors, TIM-3 inhibitors, LAG-3 inhibitors, VISTA inhibitors, STING agonists, IDO inhibitors, adenosine receptor modulators, CD39 inhibitors, CD73 inhibitors, antagonists of the chemokine receptors, especially CXCR1, CXCR2, CXCR3, CXCR4, CXCR7, CCR1, CCR2, CCR3, CCR4, CCR5, CCR7, CCR7, CCR9, CX3CR1 and CXCR6, and combinations thereof.
34. The compound of claim 1 , selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
35. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
36. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
37. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.
38. The compound of claim 1 , having the structure:
or a pharmaceutically acceptable salt thereof.