# US 2021/0276955 A1 · Deuterated compounds as immunomodulators

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- Number: US 2021/0276955 A1
- Document ID: US20210276955A1
- Status: Published application
- Kind: A1
- Application number: 17/066,986
- Filed: 2020-10-09
- Published: 2021-09-09
- Earliest claimed: 2017-10-30
- Assignees: ChemoCentryx, Inc.
- Applicants: Chemocentryx, Inc.
- Inventors: Pingchen FAN; Rebecca M. LUI; Venkat Reddy MALI; Rajinder SINGH; Yibin ZENG; Penglie ZHANG
- Web page: https://patentgrep.com/patent/US20210276955A1

## CPC

- 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
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07B 2200/05: Isotopically modified compounds, e.g. labelled
- 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
- 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)
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Compounds are provided to modulate the C5a receptor. The compounds have the following Formula (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2 and R3 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

### Claim 1

A compound of Formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from the group consisting of CH3, CH2D, CHD2, and CD3, and CD2OH;
R2 is selected from the group consisting of CH3, CH2D, CHD2, CD3, CH2OH, CDHOH, and CD2OH;
R3 is H or D;
R4 is H or D;
m is an integer from 0-6;
n is an integer from 0-3;
o is an integer from 0-4;
p is an integer from 0-9; and
q is an integer from 0-3;
and wherein said compound has at least one deuterium atom present in an amount of at least 80%.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R1 is selected from the group consisting of CH3 and CD3.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R2 is selected from the group consisting of CH3, CD3, CH2OH and CD2OH.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R3 is D.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein R3 and R4 are each H.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein the subscript n is 0, 1 or 2.

### Claim 7 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein the subscript o is 0 or 1.

### Claim 8 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein the subscript q is 0 or 1.

### Claim 9 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein the subscript p is 0, 1, 4 or 9.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt thereof wherein the subscript m is 0; the subscript n is 0, 1 or 2; the subscript o is 0 or 1; the subscript p is 0, 1, 4 or 9; and the subscript q is 0 or 1.

### Claim 12 (depends on 1)

The compound of claim 1, which is in the form of a pharmaceutically acceptable salt.

### Claim 13 (depends on 1)

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

### Claim 14 (depends on 13)

The pharmaceutical composition of claim 13, formulated for oral, intravenous, transdermal or subcutaneous administration.

### Claim 15 (depends on 13, 14)

The pharmaceutical composition of claim 13 or 14, further comprising one or more additional therapeutic agents.

### Claim 16 (depends on 15)

The pharmaceutical composition of claim 15, 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, 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.

### Claim 17 (depends on 15)

The pharmaceutical composition of claim 15, wherein the one or more additional therapeutic agent is selected from the group consisting of obinutuzumab, rituximab, ocrelizumab, cyclophosphamide, prednisone, hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, prednisolone, methylprednisolone, triamcinolone acetonide, triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinolone acetonide, halcinonide, betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone-17-valerate, halometasone, alclometasone dipropionate, beclomethasone, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone caproate, fluocortolone pivalate, fluprednidene acetate, hydrocortisone-17-butyrate, hydrocortisone-17-aceponate, hydrocortisone-17-buteprate, ciclesonide and prednicarbate, GB-0998, immuglo, begelomab, alefacept, aldesleukin, gevokizumab, daclizumab, basiliximab, inolimomab, beperminogene perplasmid, sirukumab, tocilizumab, clazakizumab, mepolizumab, fingolimod, panobinostat, triciribine, nilotinib, imatinib, tofacitinib, momelotinib, peficitinib, itacitinib, infliximab, PEG-bHb-CO, etanercept, ixazomib, bortezomib, muromonab, otelixizumab, gusperimus, brentuximab vedotin, Ponesimod, KRP-203, FG-3019, emricasan, corticotropin, ibrutinib, cinryze, conestat, methoxy polyethylene glycol-epoetin beta, belimumab, blisibimod, atacicept, seliciclib, neihulizumab, everolimus, sirolimus, denileukin diftitox, LMB-2, natalizumab, catridecacog, ciclosporin, tacrolimus, voclosporin, voclosporin, canakinumab, mycophenolate, mizoribine, CE-1145, TK-DLI, abatacept, belatacept, olmesartan medoxomil, sparsentan, TXA-127, BIIB-023, alemtuzumab, pentostatin, itolizumab, palifermin, leflunomide, PRO-140, cenicriviroc, fostamatinib, anifrolumab, sifalimumab, BAX-069, BG-00011, losmapimod, QPI-1002, ShigamAbs, TZ-101, F-652, reparixin, ladarixin, PTX-9908, aganirsen, APH-703, sotrastaurin, sotrastaurin, milatuzumab, SM-101, T-Guard, APG-101, DEX-M74, cardiotrophin-1, tiprelestat, ASKP-1240, BMS-986004, HPH-116, KD-025, OPN-305, TOL-101, defibrotide, pomalidomide, Thymoglobulin, laquinimod, remestemcel-L, Equine antithymocyte immunoglobulin, Stempeucel, LIV-Gamma, Octagam 10%, t2c-001, 99mTc-sestamibi, Clairyg, Prosorba, pomalidomide, laquinimod, teplizumab, FCRx, solnatide, foralumab, ATIR-101, BPX-501, ACP-01, ALLO-ASC-DFU, irbesartan+propagermanium, ApoCell, cannabidiol, RGI-2001, saratin, anti-CD3 bivalent antibody-diphtheria toxin conjugate, NOX-100, LT-1951, OMS721, ALN-CC5, ACH-4471, AMY-101, Acthar gel, and CD4+CD25+ regulatory T-cells, MEDI7814, P32, P59, CCX354, CCX721, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX587, CCX624, CCX282, CCX025, CCX507, CCX430, CCX765, CCX758, CCX771, CCX662, CCX650, and combinations thereof.

### Claim 18 (depends on 1)

A method of treating a human suffering from or susceptible to a disease or disorder involving pathologic activation of C5a receptors, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.

### Claim 19

(canceled)