# US 11,999,698 B2 · Fused piperidinyl bicyclic and related compounds as modulators of C5a receptor

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- Number: US 11,999,698 B2
- Document ID: US11999698B2
- Status: Granted
- Kind: B2
- Application number: 17/470,980
- Filed: 2021-09-09
- Published: 2021-12-30
- Granted: 2024-06-04
- Earliest claimed: 2019-03-11
- Assignees: InflaRx GmbH
- Applicants: InflaRx GmbH
- Inventors: Yong Li; Renfeng Guo; Niels Christoph Riedemann
- Web page: https://patentgrep.com/patent/US11999698B2

## CPC

- C07D 215/54: attached in position 3
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to fused piperidinyl bicyclic, meta-substituted piperidinyl and their related compounds that modulate activities of mammalian C5a receptor by directly binding to the C5a receptor. The invention also relates to pharmaceutical compositions containing such compounds and their use in the treatment of a disease or a disorder involving pathogenic activation of C5a receptors.

## Claims

### Claim 1

A compound having the general formula (XXI)
and pharmaceutically acceptable salts, hydrates and rotamers thereof;
wherein
C1 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R1 substituents;
C2 is selected from the group consisting of aryl and heteroaryl, wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups are optionally substituted with from 1 to 3 R2 substituents;
C3 is selected from the group consisting of C1-8 alkyl or heteroalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-4 alkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4 alkyl, heterocycloalkyl or heterocycloalkyl-C1-4 alkyl, wherein the heteroalkyl group has from 1-3 heteroatoms selected from N, O and S, wherein the heterocycloalkyl group or portion has from 1-3 heteroatoms selected from N, O and S, and wherein the heteroaryl group has from 1-3 heteroatoms as ring members selected from N and S, and each C3 is optionally substituted with from 1 to 3 R3 substituents;
each R1 is independently selected from the group consisting of halogen, —CN, —CO2Ra, —CONRaRb, —C(O)Ra, —OC(O)NRaRb, —NRbC(O)Ra, —NRbC(O)2Rc, —NRa—C(O)NRaRb, —NRaC(O)NRaRb, —NRaRb, —ORa, and —S(O)2NRaRb; wherein each Ra and Rb is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo; each Re is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Ra, Rb and Rc are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups; and
optionally when two R1 substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic or heterocyclic ring;
each R2 is independently selected from the group consisting of halogen, —CN, —NO2, —Rf, —CO2Rd, —CONRdRe, —C(O)Rd, —OC(O)NRdRe, —NReC(O)Rd, —NReC(O)2Rf, —NRdc(O)NRdRe, —NRdRe, —ORd, and —S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and is optionally substituted with one or two oxo; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, alkylamino and dialkylamino groups, and optionally when two R2 groups are on adjacent atoms, they are combined to form a five- or six-membered ring;
each R3 is independently selected from the group consisting of halogen, —CN, —Ri, —CO2Rg, —CONRgRh, —C(O)Rg, —C(O)Rj, —OC(O)NRgRh, —NRhC(O)Rg, —NRhCO2Ri, —NRgC(O)NRgRh, —NRgRh, —ORg, —S(O)2NRgRh, —O—X4Rj, —X4—NRgRh, —X4—CONRgRh, —X4—NRhC(O)Rg, X4—CO2Rg, —O—X4—CO2Rg, —NH—X4—CO2Rg, —X4—NRhCO2R, —O—X4—NRhCO2Ri, —NHRj and —NHCH2Rj, wherein X4 is a C1-4 alkylene; each Rg and Rh is independently selected from hydrogen, C1-8 alkyl or heteroalkyl, C3-6 cycloalkyl and C1-8 haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a four-, five- or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each Ri is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl; and
each Rj is selected from the group consisting of C3-6 cycloalkyl, imidazolyl, pyrimidinyl, pyrrolinyl, pyrrolyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, and S,S-dioxo-tetrahydrothiopyranyl, and wherein the aliphatic and/or cyclic portions of Rg, Rh, Ri and are optionally further substituted with from one to three halogen, methyl, CF3, hydroxy, C1-4 alkoxy, C1-4 alkoxy-C1-4 alkyl, —C(O)O—C1-8 alkyl, amino, alkylamino and dialkylamino groups, and optionally when two R3 groups are on adjacent atoms, they are combined to form a five- or six-membered ring;
X is hydrogen or CH3; and
R8 is selected from the group consisting of chloro, C2-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy;
R9 is selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, C1-C8 haloalkyl, and C1-C8 alkoxy; or
R8 and R9 are combined to form a fused saturated or unsaturated mono- or multi-ring carbocycle in which one or more of the ring carbon atoms may be replaced independently from each other by N, S, or O.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein X is hydrogen.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the compound has formula (XXIa)

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the compound has formula (I) or formula (XI):
wherein
R4 is selected from the group consisting of cyano, halo, nitro, hydroxyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, (C1-C6)alkyl-OH, (C1-C6)-alkyl-NR5R6, trifluoromethyl, (C1-C6)alkoxy, (C1-C6)thioalkoxy, phenoxy, COR7, NR5R6, NHCO(C1-C6) alkyl, SO3H, SO2(C1-C6) alkyl and SO2NR5R6;
R5 and R6 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl and (C3-C6)cycloalkyl;
R7 is independently hydroxyl, (C1-C6)alkoxy, phenoxy or —NR5R6;
m is 0-4; and
CYCLE is a saturated or unsaturated mono- or multi-ring carbocycle in which one or more of the ring carbon atoms may be replaced independently from each other by N, S, or O.

### Claim 5 (depends on 4)

The compound according to claim 4, wherein the compound has a formula selected from the group consisting of (II), (IIIa), (IIIb), (IIIc), and (IIId):

### Claim 6 (depends on 1)

The compound according to claim 1, wherein C1 is
wherein
n is an integer selected from 0, 1, 2, or 3.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein C2 is
wherein
is an integer selected from 0, 1, 2, or 3.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein C3 is
wherein
p is an integer selected from 0, 1, 2, or 3.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R8 is selected from the group consisting of chloro, C2-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein the compound is selected from the group consisting of

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to claim 1.

### Claim 12 (depends on 4)

The compound according to claim 4, wherein the compound has formula (Ia) or formula (XIa):

### Claim 13 (depends on 5)

The compound according to claim 5, wherein the compound has a formula selected from the group consisting of (IIa), (IIIe), (IIIf), (IIIg), and (IIIh):

### Claim 14 (depends on 9)

The compound according to claim 9, wherein R8 is selected from the group consisting of chloro, trifluoromethyl, and methoxy.