WO2023232870A1

WO2023232870A1 - Rorg/rorgt modulators for the treatment of virus infections like covid-19

Info

Publication number: WO2023232870A1
Application number: PCT/EP2023/064547
Authority: WO
Inventors: Hella KOHLHOF; Christian Gege; Andreas Mühler; Daniel Vitt
Original assignee: Immunic Ag
Priority date: 2022-05-31
Filing date: 2023-05-31
Publication date: 2023-12-07

Abstract

The present invention relates to the use of retinoic acid-related orphan receptor gamma (RORγ) or RORγt modulators in the treatment of virus infections, including coronavirus infections such as COVID- 19.

Description

RORg/RORgt MODULATORS FOR THE TREATMENT OF VIRUS INFECTIONS LIKE COVID-19

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the use of retinoic acid-related orphan receptor gamma (RORy) or RORyt modulators in the treatment of virus infections, including coronavirus infections such as COVID- 19.

BACKGROUND OF THE INVENTION

RORy/RORyt

The IL- 17 family of cytokines has been associated with the pathogenesis of autoimmune diseases and is generally blamed for the pathogenic symptoms of autoimmune and chronic inflammation. Overexpression of IL- 17 is a hallmark of autoimmune and chronic inflammatory diseases like rheumatoid arthritis, psoriasis and psoriatic arthritis, ankylosing spondylitis, inflammatory bowel disease, multiple sclerosis, vasculitis and atherosclerosis, systemic lupus erythematosus, as well as lung disorders, asthma and chronic obstructive pulmonary diseases (Nat. Rev. Drug Discov. 2012; 11:763). The IL- 17 cytokine family comprises six members, out of which IL-17A and IL-17F are the best characterized. IL-17A and IL-17F are clearly associated with inflammation, whereas the role of the other IL-17 family members is less explored (Cytokine Growth Factor Rev. 2010;21:413). Secretion of IL-17 is mainly caused by a specific subtype of T helper cells termed TH17 cells. Differentiation of naive CD4⁺ T cells into TH 17 cells is induced in the presence of the cytokines IL- IB, TGFP and IL-6, whereas IL- 23 maintains TH17 cell survival. Important transcription factors for the transcription and secretion of IL- 17 from TH 17 cells are retinoic acid-related orphan receptor gamma (RORyt) and STAT3. IL- 17 itself induces production of effector molecules in IL-17R expressing cells like endothelial cells, epithelial cells or fibroblasts, macrophages and dendritic cells, chondrocytes and osteoblasts. Those effector molecules are pro-inflammatory cytokines (IL-6, TNFa and IL- 1 ), chemokines (like CXCL1, CXCL2, CXCL5, CCL2, CCL7 and CCL20), growth factors (G-CSF, GM-CSF) and nitric oxide, prostaglandin E2 and matrix-metalloproteinases. Initiated by these effector molecules, neutrophil infiltration, tissue damage and chronic inflammation occurs (Nat. Rev. Drug Discov. 2012;l 1:763).

Before the recognition of the importance of IL-17 in autoimmune inflammation, IFNy derived from THI cells was believed to be the important cytokine that drives autoimmune disorders. IFNy transcription and secretion from THI effector cells is regulated by the transcription factors T-bet and STAT4. As an effector cytokine of THI immunity, IFNy is the key regulator of macrophage activation. In parallel, IFNy signalling generates other cytokines and inflammatory factors to sustain inflammation, maintain THI responses and inhibit differentiation of regulatory T cells, TH2 cells and TH 17 cells (Discov. Med. 2013;16:123; J. Biol. Chem. 2017;292:13925). Recently, the existence of hybrid TH1/TH17 cells was described. These cells can be induced in vitro by IL-23 and IL-6 in concert with IL-1 and secrete IL- 17 and IFNy. It was demonstrated that these double producing cells harbor pronounced pro-inflammatory properties and are involved in the pathogenesis of inflammatory bowel disease, experimental autoimmune encephalomyelitis and type 1 diabetes.

The effectiveness of blocking IL- 17 signalling alone as therapeutic treatment in autoimmune diseases has already been proven in clinical trials with e.g. monoclonal antibodies against IL-17A (sekukinumab or ixekizumab) and/or the IL- 17 receptor IL-17RA (brodalumab). On the other hand, blocking the IFNy signalling alone in autoimmune diseases with IFNy-specific monoclonal antibody AMG811 was investigated in clinical trials for systemic and discoid lupus erythematosus without significant clinical benefit so far.

Compounds which target and suppress both IL- 17 and IFNy are therefore reported to be predestined for the treatment of autoimmune disorders.

Of note, a second isoform of RORy exist beside RORyt, which is an elongated form with a longer amino terminal domain and this isoform is expressed in many tissues, including thymus, lung, liver, kidney, muscle and brown fat. Since both isoforms have the same ligand binding domain (LBD), a small molecule compound always modulates both isoforms in a similar manner.

Coronaviruses

Coronaviruses (CoVs) are positive-sense, single-stranded RNA (ssRNA) viruses of the order Nidovirales in the family Coronaviridae. The four sub-types of coronaviruses are alpha, beta, gamma and delta. Mostly the Alphacoronaviruses and Betacoronaviruses infect mammals, including humans. Over the last two decades, three significant novel coronaviruses have emerged which jumped from a non-human mammal hosts to infect humans: the severe acute respiratory syndrome (SARS-CoV-1) appearing in 2002, Middle East respiratory syndrome (MERS-CoV) appearing in 2012 and coronavirus disease 2019 (COVID-19, SARS-CoV-2) which appeared in late 2019. According the WHO, by end of May 2022, over 520 million people are known to have been infected resulting in over 6.2 million fatalities.

COVID-19

Coronavirus disease 2019 (COVID-19) is a contagious disease caused by one virus strain, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Symptoms of COVID-19 are variable, but often include fever, cough, headache, fatigue, breathing difficulties, loss of smell and loss of taste. Severe disease has been reported in approximately 15% of patients infected with SARS-CoV-2, of which about one third progress to critical disease (e.g. respiratory failure, shock or multi-organ dysfunction). Fully understanding the mechanism of viral pathogenesis and immune responses triggered by SARS- CoV-2 would be extremely important in rational design of therapeutic interventions beyond antiviral treatments and supportive care. Thus, there is an urgent need for novel therapies to address the different stages of the SARS-CoV-2 infectious cycle, especially to block the viral replication.

PRIOR ART

The transcription factor RORyt has been identified as the master regulator of TH 17 cell differentiation and IL- 17/22 production and is therefore an attractive target for the treatment of inflammatory or immune disorders. RORyt is exclusively expressed in the cells of the immune system (e.g., T helper cells, thymocytes and lymphoid tissue inducer cells). RORyt has been identified as the master regulator of TH17 cell differentiation and IL-17A production, as well as IL-17F and IL-22, in both innate and adaptive immune cells. IL-17A is a pro-inflammatory cytokine that contributes to chronic inflammation associated with multiple diseases including psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease and multiple sclerosis (MS). Biologies that target the IL-23/IL-17 pathway have shown significant clinical efficacy in the treatment of inflammatory diseases. Therefore, RORyt has emerged as a potentially important small molecule target for intervention in this disease-relevant pathway.

RORyt inverse agonists or agonists are mentioned, e.g. in W02016/200851 (AbbVie), WO2016/185342 (Aurigene), WO2017/102784 (AstraZeneca), WO2016/179460, W02018/089402 (BMS), WO2015/160654, WO2022/106548, WO2022/ 106549, W02022/106550, WO2022/106551 (Boehringer Ingelheim), W02012/101261, W02012/101263, WO2019/048541 (Immunic), WO2016/069974 (Janssen), WO2021/149786, WO2019/ 167982, WO2019/167981, WO2016/093342, WO2012/147916 (Japan Tobacco), WO2018/104288 (Lead Pharma/Sanofi), W02016002968 (Takeda), WO2015/116904, W02016/061160 (Vitae), WO2021/228215, WO2021228216, WO2021228217 (Shanghai Litedd), WO2023/274396 (Sunshine Lake), WO2022/122740 (Diaccurate), W02021/083311 (Reistone), WO2022/049534 (Glenmark), W02022/006074 (Dermira), W02023/016527, W02023/016528, W02023/016530 (Medshine) or W02022/007168 (Guangzhou Institutes of Medicine and Health).

Salinas et al. (PNAS 2021 ; 118:e2105927118) suggest RORyt as a cell-specific target for HIV-1 therapy since TH17 cells are highly susceptible to HIV-1 infection. They demonstrated that the pharmacological inhibition of RORyt potently suppressed HIV-1 outgrowth.

According to the present invention, we surprisingly found that RORyt/RORy modulators (i.e. RORyt/RORy inverse agonists/inhibitors as well as RORyt/RORy agonists) are able to block the viral replication of the SARS-CoV-2 independent of the presence of immune cells and are therefore suitable to mitigate or even protect from Covid-19 and not only address the hyperinflammation via TH17 in a more advanced stage of the disease.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts two representative experiments wherein Compound 8 is combined with the DHODH inhibitor Example #4. The data shows a synergistic antiviral effect on SARS-CoV-2 at different doses. Figure 2 depicts two representative experiments wherein Compound 10 is combined with the DHODH inhibitor Example #4. The data shows a synergistic antiviral effect on SARS-CoV-2 at different doses. Figure 3 depicts two representative results of an experiment wherein Compound 8 or Compound 10 is combined with the nucleoside analogue EIDD-1931 (CAS: 3258-02-4). The data shows an additive antiviral effect on SARS-CoV-2 at different doses.

SUMMARY OF THE INVENTION

The present invention relates to RORy/RORyt modulators or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a viral infection in a subject in need thereof, more preferably the viral infection is caused by a coronavirus, e.g. SARS-CoV- 2.

The RORy/RORyt modulators of the present invention surprisingly showed an antiviral activity towards SARS-CoV-2 and are therefor suitable to reduce of the viral load (or prevents infection by a virus) in the subject at an early stage of the disease.

Accordingly, the present invention relates to the prophylaxis and/or treatment of the disease, disorder, therapeutic indication or medical condition caused by a viral infection, preferably caused by a coronavirus, e.g. SARS-CoV-2.

The present invention is further directed to combination therapies with nucleoside analogues (e.g. molnupiravir) or DHODH inhibitors and is further directed to a pharmaceutical composition comprising a RORy/RORyt modulator and at least one pharmaceutically acceptable carrier or excipient.

DETAILED DESCRIPTION OF THE INVENTION

It is an object of the present invention to provide effective agents, compositions, methods and kits comprising one or more RORy/RORyt modulator(s) alone or in combination with one or more additional therapeutic agent(s), that are useful for treating viral infections, e.g. Covid- 19.

The present invention relates to a RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a viral infection in a subject in need thereof.

A particular embodiment of the present invention relates to a RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a viral infection in a subject in need thereof, wherein the viral infection is caused by a coronavirus.

A more particular embodiment of the present invention relates to a RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a coronavirus infection in a subject in need thereof, wherein the coronavirus causes a SARS or MERS infection. A most particular embodiment of the present invention relates to a RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a coronavirus infection in a subject in need thereof, wherein the coronavirus is SARS-CoV- 2.

In a particular embodiment in combination with any of the above or below embodiments the

RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof is selected from the group consisting of:

or an enantiomer, diastereomer, pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate of a salt.

In a more particular embodiment in combination with any of the above or below embodiments the RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof is selected from the group consisting of:

or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate of a salt.

One embodiment is the compound

(4-(6-(2-chloro-6-cyclopropylbenzoyl)imidazo[l,5-a]pyrimidin-8-yl)-2-hydroxybenzoic acid; CAS

1677668-27-7) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 1”, which is disclosed in W02015/036411 as Example 91.

One embodiment is the compound

(4-(l-(2-chloro-6-(trifhioromethyl)benzoyl)-177-indazol-3-yl)benzoic acid; CAS 1392809-08-3) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 2”, which is disclosed in WO2012/106995 as Example 1 IM.

One embodiment is the compound

((7?)-2-acetyl-A-(4-(l , 1 , 1 ,3 ,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-5-(methylsulfonyl)iso- indoline-1 -carboxamide; CAS 2101291-07-8) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 3”, which is disclosed in WO2017/102784 as Example 451.

One embodiment is the compound

((S)-A-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-7-isopropyl-6-(((lr,4<S)-4-(trifluoromethyl)cyclo- hexyl)methyl)-6,7-dihydro-577-pyrrolo [3, 4-6]pyridine-3 -carboxamide; CAS 1802706-04-2) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 4”, which is covered by WO2015/116904, WO2019/018975 and WO2019/023216.

One embodiment is the compound

((S)-A-(5-chloro-3-((4-(cyclopentanecarbonyl)-3-methylpiperazin-l-yl)methyl)-2-methylphenyl)-2- methylpyrimidine-5-carboxamide; CAS 1613329-90-0) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as

“Compound 5”, which is disclosed in WO2014/086894 as Example 192.

One embodiment is the compound

((5)-A-(8-((4-(cyclopentanecarbonyl)-3 -methylpiperazin- 1 -yl)methyl)-7 -methylimidazo [ 1 ,2-a]pyridin- 6-yl)-2-methylpyrimidine-5-carboxamide; CAS 2079892-79-6) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 6”, which is disclosed in ChemMedChem 2016; 11:2640.

One embodiment is the compound

(l-(2,6-dichlorophenyl)-2-(furan-2-yl)-4-isobutyl-5-methyl-l//-imidazole; CAS 2581110-01-0) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 7”, which is disclosed in JCI Insight

2017;2:e91127 and J. Med. Chem. 2019;62:10816.

One embodiment is the compound

(2-( 1 -(2,4-dichloro-3 -((7 -chloro-5 -(trifhioromethyl)- lH-indol- 1 -yl)methyl)benzoyl)piperidin-4- yl)acetic acid; CAS 2055496-11-0) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 8”, which is disclosed in WO2016/200851 as Example EI-5.

One embodiment is the compound

(3-cyano-A-(3-(l-isobutyrylpiperidin-4-yl)-l-methyl-4-(trifluoromethyl)-177-pyrrolo[2,3-6]pyridin-5- yl)benzamide; CAS 1892576-58-7) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 9”, which is disclosed in WO2016/046755 as Example 5.

((5)-3-(6-(3-(difhroromethoxy)-5-fhiorophenyl)-4-((3-(trifhioromethyl)phenyl)sulfonyl)-3,4-dihydro- 2//-benzo[Z>][l,4]oxazin-2-yl)-2,2-dimethylpropanoic acid; CAS 2055536-64-4) or a pharmaceutically acceptable salt (e.g. the sodium salt), solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 10”, which is disclosed in WO2016/201225 as Example 32J. One embodiment is the compound

( V-(2,4-difluorophenyl)-2-(4-(2-(4-(ethylsulfonyl)phenyl)acetamido)-2-fluorophenyl)-2 -methyl- propanamide; CAS 2068119-11-7) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 11”, which is disclosed in W02017/010399 as Example 57.

One embodiment is the compound

((S)-2-(4-cyclopropyl-6-methylpyrimidin-5-yl)-8-(l-cyclopropylethyl)-6-(((5-(methylsulfonyl)pyridin- 2-yl)methyl)amino)pteridin-7(8Z/)-one; CAS 1817773-66-2) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 12”, which is disclosed in WO2015/160654 as Example 136 and of which polymorphs, solvates, salts are disclosed in WO2022/106547, WO2022/ 106548, WO2022/106549, W02022/106550 and WO2022/106551.

One embodiment is the compound

(2-chloro-6-fhioro-A-(2-((3-(trifhioromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-l//-benzo[c]azepin- 8-yl)benzamide; CAS 1826671-29-7) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 13”, which is disclosed in ChemMedChem 2016; 11:207.

One embodiment is the compound

(9-ethyl-A-(4-(ethylsulfonyl)benzyl)-977-carbazole-3 -carboxamide; CAS 2225882-89-1) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 14”, which is disclosed in WO2019/007284 as

Example 1.

One embodiment is the compound

(JV-(4-fluorobenzyl)-jV-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine-3-sulfonamide;

CAS 1638647-01-4) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 15”, which is disclosed in Bioorg. Med. Chem. Lett. 2014;24:5769.

One embodiment is the compound

((ll?,3S,42?)-4-((3a7?,9b7?)-9b-((4-fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)-2,3,3a,4,5,9b- hexahydro- 17f-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-l-carboxylic acid; CAS 2460133-35- 9) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 16”, which is disclosed in WO2016/179460. One embodiment is the compound

(3-((S)-4-(4-((17?,21?)-2-(tert-butyl)cyclopropyl)-3-chlorophenyl)-5-isopropyl-4-methyl-2-oxo-3,4- dihydropyrimidin-l(277)-yl)bicyclo[l.l.l]pentane-l -carboxylic acid; CAS 2375337-65-6) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 17”, which is disclosed in WO2019/167981. One embodiment is the compound

(3-(( )-5-(( )-5ec-butyl)-4-(4-((17?,27?)-2-(terZ-butyl)cyclopropyl)-3-chlorophenyl)-4-methyl-2-oxo- 3,4-dihydropyrimidin-l(277)-yl)bicyclo[l.l.l]pentane-l-carboxylic acid; CAS 2375337-66-7) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 18”, which is disclosed in WO2019/167981. One embodiment is the compound

((5)-3-(4-(3-chloro-4-(3,3-dimethylbutyl)phenyl)-5-isopropyl-4-methyl-2-oxo-3,4-dihydropyrimidin- l(277)-yl)propanoic acid; CAS 1950570-48-5) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 19”, which is disclosed in WO2016/093342.

One embodiment is the compound

2-(( 1 S,3s)-3 -((7?)-5 -((7-fluoro- 1 , 1 -dimethyl-2, 3 -dihydro- 177-inden-5 -yl)carbamoyl)-2-methoxy- 5,6,7,8-tetrahydro-l,6-naphthyridine-6-carbonyl)cyclobutyl)acetic acid; CAS 1854901-94-2) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 20”, which is disclosed in WO2016/002968 and JP2020152649.

One embodiment is the compound

(6-methoxy-5-morpholino-2-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3-dihydro-l//-inden-l-one;

CAS 1675206-11-7) or an enantiomer, pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 21”, which is disclosed in W02015/038350.

One embodiment is the compound

((5)-5-(2,3-dichloro-4-(l , 1 , 1 ,3 , 3, 3-hexafluoro-2-hydroxypropan-2-yl)phenyl)-A-(2 -hydroxy-2 -methyl- propyl)-4-(2-methylpyrrolidine-l-carbonyl)thiazole-2-carboxamide; CAS 1917306-06-9) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 22”, which is disclosed in WO2016/069974. One embodiment is use of the compound

(A-(6-(2,6-dimethylpyrimidin-4-yl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)-2-(4-(ethylsulfonyl)phenyl)acetamide; CAS 2048999-76-2) or an enantiomer, pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 23”, which is disclosed in WO2016/185342.

One embodiment is the compound

(6-(2,6-dimethylpyrimidin-4-yl)-7V-(4-(ethylsulfonyl)benzyl)-6-methyl-5-oxo-5,6,7,8-tetrahydro- quinoline-2-carboxamide; CAS 2049004-03-5) or an enantiomer, pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 24”, which is disclosed in WO2016/185342.

One embodiment is the compound

(2-(4-((cyclopropylmethyl)sulfonyl)phenyl)-7V-(4-(l , 1 ,1 ,3,3-pentafhioro-2-hydroxypropan-2- yl)phenyl)acetamide; CAS 2229935-97-9, 2229936-01-8 and 2229936-00-7) or an enantiomer, pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 25”, which is disclosed in WO2018/104288. One embodiment is the compound

(2-(4-((cyclopropylmethyl)sulfmyl)phenyl)-A-(4-(l , 1 , l,3,3-pentafluoro-2-hydroxypropan-2- yl)phenyl)acetamide; CAS 2229936-07-4, 2229936-06-3, 2229936-05-2, 2229936-04-1 and 2229936- 02-9) or an enantiomer, diastereomer, pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 26”, which is disclosed in WO2018/104288.

One embodiment is the compound

((/?)- 3 -cyano-A-(3 -(1 -(cyclopentanecarbonyl)-2,2-dimethylpiperidin-4-yl)- 1 ,4-dimethyl- 1H- pyrrolo[2,3-6]pyridin-5-yl)benzamide; CAS 2229936-07-4) or a pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 27”, which is disclosed in WO2016/046755.

One embodiment is the compound

(JV-((5-(ethylsulfonyl)pyridin-2-yl)methyl)-5'-methyl-l-(l-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)- 4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-2'-carboxamide; CAS 2088333-60-0, 2088333- 59-7, 2088333-58-6 and 2088333-57-5) or an enantiomer, diastereomer, pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 28”, which is disclosed in WO2017/044410.

One embodiment is the compound

(4-(4-(3-(2-chloro-6-fluorophenyl)-4-(pyrimidin-2-yl)isoxazol-5-yl)-5-(trifluoromethyl)-177-pyrazol-l- yl)-2-methylbutan-2-ol; CAS 2299252-72-3) or an pharmaceutically acceptable salt, solvate or solvate of a salt thereof, for use in the treatment of a viral infection, hereinafter also referred to as “Compound 29”, which is disclosed in WO2019/048541.

In a particular embodiment in combination with any of the above or below embodiments the RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof results in the reduction of the viral load in the subject.

In a more particular embodiment in combination with any of the above or below embodiments the administration of the RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof is executed within the first 8 days after detection of the coronavirus infection or onset of symptoms, more preferably within the first 5 days, most preferably within the first 3 days.

An embodiment in combination with any of the above or below embodiments relates to a RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof, wherein the subject has had a known contact with a patient who has been diagnosed with a coronavirus, such as a SARS-CoV-2 infection.

An embodiment in combination with any of the above or below embodiments relates to a RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof, wherein the subject begins administration of the RORy/RORyt modulator prior to being diagnosed with a coronavirus, especially a SARS-CoV-2 infection.

A particular embodiment in combination with any of the above or below embodiments relates to a RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof, wherein the administration of the RORy/RORyt modulator results in one or more clinical benefits.

In an more particular embodiment in combination with any of the above or below embodiments relates to a RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof, wherein the administration of the RORy/RORyt modulator results in one or more clinical benefits, which is/are selected from shortening the duration of infection, reduction of the likelihood of hospitalization, reduction in the likelihood of mortality, reduction in the likelihood of Intensive Care Units (ICU) admission, reduction in the likelihood being placed on mechanical ventilation, reduction in the likelihood supplemental oxygen will be needed, reduction in the likelihood of having long-Covid symptoms, and/or reduction in the length of hospital stay.

In an embodiment in combination with any of the above or below embodiments the RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof is administered orally.

In a particular embodiment in combination with any of the above or below embodiments the RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof is administered for about 5 days to about 21 days. In a particular embodiment in combination with any of the above or below embodiments the RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof acts as a RORy/RORyt inverse agonist.

Also provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient.

Also provided is a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier or excipient and further comprising one or more additional therapeutic agents selected from antiinflammatory agents, antiviral agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal antiinflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

In a particular embodiment in combination with any of the above or below embodiments the additional therapeutic agent in the pharmaceutical composition is a nucleoside analogue (e.g. molnupiravir), protease inhibitor (e.g. nirmatrelvir/ritonavir) or a DHODH inhibitor, more preferably a DHODH inhibitor (e.g. vidofludimus calcium).

The present invention further refers to the method of treatment of viral infections comprising administering a compound according to any of the preceding embodiments.

The present invention further refers to the use of a compound according to any of the preceding embodiments in the method of treatment of viral infections.

The present invention further relates to the use of a compound according to any of the preceding embodiments for the manufacture of a medicament for the treatment of viral infections.

In certain embodiments the present invention relates to a RORy/RORyt modulator as described in the following items:

1. A RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a viral infection in a subject in need thereof.

2. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a viral infection in a subject in need thereof according to item 1, wherein the viral infection is caused by a coronavirus.

3. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a coronavirus infection in a subject in need thereof according to item 2, wherein the coronavirus causes a SARS or MERS infection.

4. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of items 1 to 3, wherein the coronavirus is SARS-CoV-2. 5. The RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof according to any one of items 1 to 4, wherein the RORy/RORyt modulator is selected from the group consisting of:

6. The RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof according to any one of items 1 to 4, wherein the RORy/RORyt modulator is selected from the group consisting of:

7. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of items 1 to 6, wherein the administration of the RORy/RORyt modulator results in the reduction of the viral load in the subject.

8. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of items 2 to 7, wherein the administration of the RORy/RORyt modulator is executed within the first 5 days after detection of the coronavirus infection or onset of symptoms.

9. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of items 2 to 8, wherein the subject has had a known contact with a patient who has been diagnosed with a coronavirus, such as SARS-CoV-2 infection.

10. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of items 2 to 8, wherein the subject begins administration of the RORy/RORyt modulator prior to being diagnosed with a coronavirus, especially SARS-CoV-2 infection. 11. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of items 2 to 8, wherein the administration of the RORy/RORyt modulator results in one or more clinical benefits.

12. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of items 1 to 11, wherein the RORy/RORyt modulator is administered orally.

13. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of items 1 to 12, wherein the RORy/RORyt modulator is administered for about 5 days to about 21 days.

14. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of items 1 to 13, wherein the RORy/RORyt modulator acts as a RORy/RORyt inverse agonist.

15. A pharmaceutical composition comprising the RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof according to any of items 1 to 14 together with a pharmaceutically acceptable carrier or excipient.

16. A pharmaceutical composition of item 15, further comprising one or more additional therapeutic agents selected from antiinflammatory agents, antiviral agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal antiinflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

17. A pharmaceutical composition of item 16, wherein the additional therapeutic agent is a DHODH inhibitor.

18. A method of treating a viral infection in a subject in need thereof, comprising administering a RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof.

19. The method of treating a viral infection in a subject in need thereof according to item 18, wherein the viral infection is caused by a coronavirus. 20. The method of treating a viral infection in a subject in need thereof according to item 19, wherein the coronavirus causes a SARS or MERS infection.

21. The method of treating a viral infection in a subject in need thereof according to any one of items 18 to 20, wherein the coronavirus is SARS-CoV-2.

22. The method of treating a viral infection in a subject in need thereof according to any one of items

18 to 21, wherein the RORy/RORyt modulator is selected from the group consisting of:

23. The method of treating a viral infection in a subject in need thereof according to any one of items 18 to 21, wherein the RORy/RORyt modulator is selected from the group consisting of:

24. The method of treating a viral infection in a subject in need thereof according to any one of items 18 to 23, wherein the administration of the RORy/RORyt modulator results in the reduction of the viral load in the subject.

25. The method of treating a coronavirus infection in a subject in need thereof according to any one of items 19 to 24, wherein the administration of the RORy/RORyt modulator is executed within the first 5 days after detection of the coronavirus infection or onset of symptoms.

26. The method of treating a coronavirus infection in a subject in need thereof according to any one of items 19 to 25, wherein the subject has had a known contact with a patient who has been diagnosed with a coronavirus, such as SARS-CoV-2 infection.

27. The method of treating a coronavirus infection in a subject in need thereof according to any one of items 19 to 25, wherein the subject begins administration of the RORy/RORyt modulator prior to being diagnosed with a coronavirus, especially SARS-CoV-2 infection.

28. The method of treating a coronavirus infection in a subject in need thereof according to any one of items 19 to 25, wherein the administration of the RORy/RORyt modulator results in one or more clinical benefits. 29. The method of treating a viral infection in a subject in need thereof according to any one of items 18 to 28, wherein the RORy/RORyt modulator is administered orally.

30. The method of treating a viral infection in a subject in need thereof according to any one of items 18 to 29, wherein the RORy/RORyt modulator is administered for about 5 days to about 21 days.

31. The method of treating a viral infection in a subject in need thereof according to any one of items 18 to 30, wherein the RORy/RORyt modulator acts as a RORy/RORyt inverse agonist.

32. The method of treating a viral infection in a subject in need thereof according to any one of claims 18 to 31, further comprising administering one or more additional therapeutic agents selected from antiinflammatory agents, antiviral agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal antiinflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

33. The method of treating a viral infection in a subject in need thereof according to item 32, wherein the additional therapeutic agent is a DHODH inhibitor.

DEFINITIONS

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Thus, the compounds of the present disclosure which contain acidic groups can be present on these groups and can be used according to the disclosure, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic base in a solvent or dispersant, or by cation exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

The term "solvate" refers to a crystalline form of a molecule that further comprises molecules of a solvent or solvents incorporated into the crystalline lattice structure. Thus, the compounds of the present disclosure may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol. A stoichiometric or non- stoichiometric amount of solvent is bound by non-covalent intermolecular forces. When the solvent is water, the "solvate" is a "hydrate." It is understood, that a "pharmaceutically acceptable salts" can in addition optionally contain a "solvate".

The term "polymorph" as used herein refers to a crystalline form of a compound or a salt, hydrate, or solvate thereof, in a particular crystal packing arrangement. All polymorphs have the same elemental composition. The term "crystalline" as used herein, refers to a solid state form which consists of orderly arrangement of structural units. Different crystalline forms of the same compound, or a salt, hydrate, or solvate thereof, arise from different packing of the molecules in the solid state, which results in different crystal symmetries and/or unit cell parameter. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability and solubility.

The compounds of the invention may, depending on their structure, exist in tautomeric or stereoisomeric forms (enantiomers, diastereomers). The invention therefore also encompasses the tautomers, enantiomers or diastereomers and respective mixtures thereof. The stereoisomerically uniform constituents can be isolated in a known manner from such mixtures of enantiomers and/or diastereomers. The term “diastereomer” means stereoisomers that are not mirror images of one another and are non- superimposable on one another. The term “enantiomer” means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e. at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.

As used herein, the term “RORy/RORyt modulator” refers to a substance that binds to RORy/RORyt and regulates its activity in a positive or negative direction (i.e. RORyt/RORy inverse agonists/inhibitors as well as RORyt/RORy agonists).

As used herein, the term “subject” refers to any member of the animal kingdom including humans. In some embodiments, “subject” refers to humans, at any stage of development. In some embodiments, “subject” refers to a human patient. In some embodiments, “subject” refers to non-human animals. In some embodiments, the non-human animal is a mammal (e.g. a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate or a pig). In some embodiments, subjects include, but are not limited to, mammals, birds, reptiles, amphibians, fish or worms. In some embodiments, a subject may be a transgenic animal, genetically-engineered animal or a clone.

As used herein, the term "treating" includes, but is not limited to, methods and manipulations to produce beneficial changes in a recipient's health status. The changes can be either subjective or objective and can relate to features such as symptoms or signs of the viral infection being treated. Preventing the deterioration of a recipient's status is also included by the term. Treating, as used herein, also includes administering a RORy/RORyt modulator alone or in combination with an additional therapeutic agent to a subject having a viral infection or is at risk of becoming a viral infection.

As used herein, the term "administering" includes activities associated with providing a patient an amount of a compound described herein, e.g. a RORy/RORyt modulator. Administering includes providing unit dosages of compositions set forth herein to a patient in need thereof. Administering includes providing effective amounts of compounds, e.g. a RORy/RORyt modulator, for a specified period of time, e.g. for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or more days, or in a specified sequence, e.g. administration a RORy/RORyt modulator followed by the administration of one or more antiviral drugs, or vice versa.

As used herein, the term "co-administering" includes sequential or simultaneous administration of two or more structurally different compounds. For example, two or more structurally different pharmaceutically active compounds can be co-administered by administering a pharmaceutical composition adapted for oral administration that contains two or more structurally different active pharmaceutically active compounds. As another example, two or more structurally different compounds can be co-administered by administering one compound and then administering the other compound. In some instances, the co-administered compounds are administered by the same route. In other instances, the co-administered compounds are administered via different routes. For example, one compound can be administered orally, and the other compound can be administered, e.g. sequentially or simultaneously, via intravenous or intraperitoneal injection.

As used herein the viral infection, especially acute viral infection, is selected from coronavirus infections, SARS-CoV-2 (COVID-19), SARS, flu/influenza (and avian influenza), HIV/Aids, chickenpox (Varicella), cytomegalovirus, Dengue Fever, German measles (Rubella), hand-foot-mouth disease, hantavirus infections, all forms of hepatitis, Lassa fever, Marburg virus infections, measles, meningitis, MERS-CoV, mumps, norovirus infections, herpes simplex virus infections, smallpox, monkeypox, rotavirus infections, Ebola virus, poliovirus infections, rhinovirus infections, parainflunenzavirus infections, RSV infections, HCMV infections and bannavirus infections. More preferred is SARS-CoV-2 (COVID-19), flu/influenza and rhinovirus infections, most preferred is SARS-CoV-2 (COVID-19). It is understood, that also mutated forms of the virus (e.g. of SARS-CoV- 2) are covered.

SARS-CoV-2 is constantly mutating, which many increase virulence and transmission rates. Drugresistant variants of viruses may emerge after prolonged treatment with an antiviral agent. Drug resistance may occur by mutation of a gene that encodes for an enzyme used in viral replication. The efficacy of a drug against an RNA virus infection in certain cases can be prolonged, augmented or restored by administering the compound in combination or alternation with another and perhaps even two or three other, antiviral compounds that induce a different mutation or act through a different pathway, from that of the principle drug. A variant of a known virus can refer to a virus carrying one or more nucleotide mutations in the viral genome as compared to the known virus, for instance at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 60, 100, 200, 300 or even more nucleotide mutations. Mutations can refer to nucleotide deletion, insertion, or substitution. In some cases, a variant can have at most 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1% of the viral genome different than the genome of a known virus. Examples of other therapeutic agents that may be combined with a RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, either administered separately, or in the same pharmaceutical composition include, but are not limited to a:

(1) Protease inhibitor (e.g. PF-07304814, PF-00835231, nirmatrelvir, lopinavir or ritonavir);

(2) Polymerase inhibitor (e.g. gemcitabine);

(3) Allosteric polymerase inhibitor;

(4) Interferon alfa-2a, which may be pegylated or otherwise modified, and/or ribavirin;

(5) Non-substrate-based inhibitor;

(6) Helicase inhibitor;

(7) Primase-helicase inhibitor (e.g. pritelivir);

(8) Antisense oligodeoxynucleotide (S-ODN);

(9) Aptamer;

(10) Nuclease-resistant ribozyme;

(11) iRNA, including microRNA and SiRNA;

(12) Antibody, partial antibody or domain antibody to the virus;

(13) Viral antigen or partial antigen that induces a host antibody response;

(14) NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3);

(15) Glutamyl-prolyl-tRNA synthetase inhibitor (e.g. halofuginone);

(16) Equilibrative nucleoside transporter (ENT) inhibitor (e.g. dipyridamole);

(17) Nucleoside analogue/RNA replication modulator (e.g. molnupiravir, bemnifosbuvir)

(17) other DHODH inhibitors (e.g. brequinar, teriflunomide, leflunomide, PTC299, MEDS433, AG- 636, ASLAN003, JNJ-74856665, RP7214, PP-001 and BAY2402234).

EXPERIMENTAL PART

The RORy/RORyt modulators “Compound 1“ to “Compound 28“ of the present invention can be prepared as outlined in mentioned patent applications or publications above, or purchased from commercial vendors.

Compound 5 : (S)-N-(5 -Chloro-3 -((4-(cyclopentanecarbonyl)-3 -methylpiperazin- 1 -yl)methyl)-2- methylphenyl)-2-methylpyrimidine-5-carboxamide

The target compound was prepared as outlined in WO2014/086894 and obtained as a white solid. *H- NMR (400 MHz, DMSO-de) 5: 10.27 (s, 1H), 9.18 (s, 2H), 7.42 (s, 1H), 7.29 (s, 1H), 4.54 (d, J = 6.8 Hz, 0.5H), 4.23-4.19 (m, 1H), 3.77 (d, J = 13.6 Hz, 0.5H), 3.50-3.43 (m, 2 H), 3.22-3.15 (m, 0.5H), 2.95-2.88 (m, 1H), 2.77-2.61 (m, 5.5H), 2.23 (s, 3H), 2.16-1.48 (m, 10H), 1.25-1.09 (m, 3H). LC-MS: 470.2 (M+H)⁺.

Compound 6: (S)-/V-(8-((4-(Cyclopentanecarbonyl)-3-methylpiperazin-l-yl)methyl)-7-methyl- imidazo[ 1 ,2-a]pyridin-6-yl)-2-methylpyrimidine-5 -carboxamide

The target compound was prepared as outlined in ChemMedChem 2016; 11 :2640 and obtained as a white solid. ^XH-NMR (400 MHz, DMSO-de) 5: 10.29 (s, 1H), 9.22 (s, 2H), 8.64 (s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.54 (d, J = 1.2 Hz, 1H), 4.53 (bs, 0.5H), 4.19-4.14 (m, 1H), 3.98-3.85 (m, 2H), 3.75-3.68 (m, 0.5H), 3.15-3.06 (m, 0.5H), 2.93-2.86 (m, 1H), 2.74-2.61 (m, 5.5H), 2.38 (s, 3H), 2.23-2.14 (m, 1H), 2.07-1.46 (m, 9H), 1.19-1.01 (m, 3H). LC-MS: 476.3 (M+H)⁺.

Compound 7: l-(2,6-Dichlorophenyl)-2-(furan-2-yl)-4-isobutyl-5-methyl-17Z-imidazole

Compound 7

The target compound was prepared as outlined in ChemMedChem 2016; 11 :2640 and obtained as a white solid. 'H-NMR (400 MHz, DMSO-de) 8: 7.78 (dd, J = 0.8, 8.0 Hz, 2H), 7.65 (dd, J = 7.6, 8.8 Hz, 1H), 7.55 (dd, J = 0.6, 1.8 Hz, 1H), 6.43 (dd, J = 2.0, 3.6 Hz, 1H), 5.99 (dd, J = 0.6, 3.4 Hz, 1H), 2.39 (d, J = 6.8 Hz, 2H), 2.00-1.91 (m, 1H), 1.87 (s, 3H), 0.91 (d, J= 6.8 Hz, 6H). LC-MS: 349.1 (M+H)⁺.

Compound 8 : 2-( 1 -(2,4-Dichloro-3 -((7 -chloro-5 -(trifluoromethyl)- IH-indol- 1 -yl)methyl)benz- oyl)piperidin-4-yl)acetic acid

The target compound was prepared as outlined in WO2016/200851 and obtained as a white solid. 'H- NMR (500 MHz, DMSO-de) 8: 12.10 (br s, 1H), 8.01 (s, 1H), 7.69 (t, J = 8.3 Hz, 1H), 7.53 (d, J = 10.0 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.03-6.95 (m, 1H), 6.73 (t, J = 3.0 Hz, 1H), 6.19-6.05 (m, 2H), 4.46 (d, J = 11.0 Hz, 1H), 3.29 (d, J = 14.0 Hz, 1H), 3.06-2.98 (m, 1H), 2.83-2.72 (m, 1H), 2.20-2.13 (m, 2H), 1.98-1.89 (m, 1H), 1.77 (d, J= 13.5 Hz, 1H), 1.60 (t, J= 13.0 Hz, 1H), 1.23-1.05 (m, 2H). LC-MS: 547.0/549.0 (M+H)⁺.

Compound 12: (5)-2-(4-Cyclopropyl-6-methylpyrimidin-5-yl)-8-(l-cyclopropylethyl)-6-(((5- (methylsulfonyl)pyridin-2-yl)methyl)amino)pteridin-7(8//)-one

The target compound was prepared as outlined in WO2015/160654 and ACS Med. Chem. Lett. 2021; 12: 143 (supporting info). ^-NMR (400 MHz, DMSO-cL) 8: 9.04 (d, J = 2.0 Hz, 1H), 8.91 (br s, 1H), 8.88 (s, 1H), 8.81 (s, 1H), 8.28 (dd, J = 8.4, 2.0 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 4.87 (d, J = 7.0 Hz, 2H), 4.72 (br s, 1H), 3.33 (s, 3H), 2.25 (s, 3H), 1.96 (br s, 1H), 1.72 (br s, 1H), 1.64 (d, J = 4.4 Hz, 3H), 1.07-1.04 (m, 2H), 0.92-0.84 (m, 2H), 0.64-0.61 (m, 1H), 0.44-0.35 (m, 2H), 0.12 (br s, 1H). LC- MS: 533.3 (M+H)⁺.

Compound 13: 2-Chloro-6-fluoro-7V-(2-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3,4,5-tetrahydro-l//- benzo[c]azepin-8-yl)benzamide

The target compound was prepared as outlined in ChemMedChem 2016; 11:207 and obtained as a white solid. 'H-NMR (500 MHz, DMSO-cL) 8: 10.77 (s, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.81 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.58-7.53 (m, 1H), 7.46 (d, J = 7.5 Hz, 2H), 7.39 (t, J = 8.8 Hz, 1H), 7.05 (d, J = 8.5 Hz, 1H), 4.50 (s, 2H), 3.62 (br s, 2H), 2.84-2.77 (m, 2H), 1.52 (br s, 2H). LC-MS: 527.2 (M+H)⁺.

Compound 14: 9-Ethyl-/V-(4-(ethylsulfonyl)benzyl)-977-carbazole-3-carboxamide

The target compound was prepared as outlined in WO2019/007284 and obtained as a white solid. ’H- NMR (500 MHz, DMSO-d₆) 8: 9.19 (t, J = 5.8 Hz, 1H), 8.77 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 8.06 (dd, J = 8.5, 1.5 Hz, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.71-7.62 (m, 4H), 7.52 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.49 (q, J = 7.0 Hz, 2H), 3.26 (q, J = 7.0 Hz, 2H), 1.34 (t, J = 7.0 Hz, 3H), 1.10 (t, J = 7.5 Hz, 3H). LC-MS: 421.3 (M+H)⁺.

Compound 15: JV-(4-Fluorobenzyl)-JV-isobutyl-6-((l-(methylsulfonyl)piperidin-4-yl)amino)pyridine- 3-sulfonamide

The target compound was prepared as outlined in Bioorg. Med. Chem. Lett. 2014;24:5769 and obtained as a white solid. ^!H-NMR (500 MHz, CDC1₃) 8 8.49 (d, J = 3.0 Hz, 1H), 7.69 (dd, J = 8.8, 2.8 Hz, 1H), 7.30-7.27 (m, 2H), 7.02-6.96 (m, 2H), 6.40 (d, J = 9.0 Hz, 1H), 4.91 (d, J = 7.5 Hz, 1H), 4.24 (s, 2H), 4.07-3.94 (m, 1H), 3.84-3.81 (m, 2H), 2.94-2.85 (m, 4H), 2.83 (s, 3H), 2.24-2.15 (m, 2H), 1.68-1.58 (m, 3H), 0.75 (d, J = 6.5 Hz, 6H). LC-MS: 499.1 (M+H)⁺.

Compound 16: (17?,3S,47?)-4-((3a/?,9b7?)-9b-((4-Fluorophenyl)sulfonyl)-7-(perfluoropropan-2-yl)- 2,3,3a,4,5,9b-hexahydro-177-benzo[e]indole-3-carbonyl)-3-methylcyclohexane-l-carboxylic acid

The target compound was prepared similar as outlined in WO2016/179460 or Org. Process Res. Dev. 2021;25:1556 and obtained as a white solid. ^JH-NMR (400 MHz, CD3OD) 8 7.99 (d, J = 8.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.34-7.29 (m, 2H), 7.26 (s, 1H), 7.07 (t, J = 8.6 Hz, 2H), 4.76 (dd, J = 4.8, 12.0 Hz, 1H), 4.05-3.99 (m, 1H), 3.91-3.85 (m, 1H), 3.57-3.51 (m, 1H), 2.74-2.45 (m, 6H), 2.03-1.85 (m, 4H), 1.81-1.73 (m, 1H), 1.61-1.43 (m, 2H), 1.35-1.24 (m, 1H), 1.08 (d, J = 7.2 Hz, 3H). LC-MS: 688.3 (M+H)⁺.

Compound 22: ( )-5-(2,3-Dichloro-4-(l,l,l,3,3,3-hexafluoro-2-hydroxypropan-2-yl)phenyl)- V-(2- hydroxy-2-methylpropyl)-4-(2-methylpyrrolidine-l-carbonyl)thiazole-2-carboxamide

The target compound was prepared as outlined in WO2016/069974 and obtained as a pale yellow solid. 'H-NMR (400 MHz, CD3OD, mixture of tautomers with a ratio of 2:1) 8 7.90 (br s, 1H), 7.58-7.55 (m, 1H), 4.55-4.53 and 4.20-4.14 (m, 1H), 3.67-3.43 (m, 4H), 2.15-1.58 (m, 4H), 1.33-1.13 (m, 9H). LC- MS: 622.0/624.0 (M+H)⁺.

Compound 23: JV-(6-(2,6-Dimethylpyrimidin-4-yl)-6-methyl-5-oxo-5,6,7,8-tetrahydroquinolin-2-yl)- 2-(4-(ethylsulfonyl)phenyl)acetamide

The target compound was prepared as outlined in WO2016/185342 and obtained as a white solid. 'H- NMR (400 MHz, CDC1₃) 5 8.38 (d, J = 8.8 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 6.78 (s, 1H), 3.82 (s, 2H), 3.12 (q, J = 7.4 Hz, 2H), 2.96-2.85 (m, 3H), 2.61 (s, 3H), 2.39 (s, 3H), 2.17-2.11 (m, 1H), 1.53 (s, 3H), 1.29 (t, J = 7.4 Hz, 3H). LC-MS: 493.3 (M+H)⁺.

Compound 24: 6-(2,6-Dimethylpyrimidin-4-yl)-A (4-(ethylsulfonyl)benzyl)-6-methyl-5-oxo-5, 6,7,8- tetrahydroquinoline-2-carboxamide

The target compound was prepared as outlined in WO2016/185342 and obtained as a white solid. *H- NMR (400 MHz, CDCI3) 8 8.54 (d, J = 8.0 Hz, 1H), 8.78 (t, J = 6.4 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 6.81 (s, 1H), 3.75 (d, J = 6.0 Hz, 2H), 3.12-3.04 (m, 4H), 2.99-2.93 (m, 1H), 2.59 (s, 3H), 2.41 (s, 3H), 2.24-2.17 (m, 1H), 1.56 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H). LC-MS: 493.3 (M+H)⁺.

Example 200: Antiviral activity on SARS-CoV-2

The assay for viral replication (YFP) and the cell viability assay has been described in general in Pathogens 2021; 10: 1076. Applied to compounds of the present invention furnished the following results:

EC50 ranges for the SARS-CoV-2 assay as described herein: +++: <5 pM; ++: 5 pM to <25 pM; +: 25 pM to <50 pM; 0: >50 pM.

Example 201: Human DHODH inhibition assay The in vitro inhibition of hDHODH was measured using an A-terminally truncated recombinant hDHODH enzyme as described in J. Med. Chem. 2006;49:1239. Briefly, the hDHODH concentration was adjusted in a way that an average slope of approximately 0.2 AU/min served as the positive control (e.g. without inhibitor). The standard assay mixture contained 60 pM 2,6-dichloroindophenol, 50 pM decylubiquinone and 100 pM dihydroorotate. The hDHODH enzyme with or without at least six different concentrations of the compounds was added and measurements were performed in 50 mM TrisHCl, 150 mM KC1 and 0.1% Triton X- 100 at pH 8.0 and at 30°C. The reaction was started by adding dihydroorotate and measuring the absorption at 600 nm for 2 min. For the determination of the IC50 values, each data point was recorded in triplicate. The IC50 values for Compound 1 to Compound 16, and Compound 22 to Compound 24 were all »100 pM with no remarkable inhibition at the highest concentration tested (100 pM). The only exception is Compound 29 with an IC50 of <1 pM on DHODH.

Example 202: Synergistic antiviral activity on SARS-CoV-2 with a DHODH inhibitor

The synergistic potential of RORy/RORyt modulator Compound 8 and Compound 10, respectively, together with the DHODH inhibitor Example #4 (filed on 23.12.2021 in EP21217534.3) was assessed.

The method of combinatorial drug assessment by a viral replication inhibition assay has been published in Pathogens 2021 ;10: 1076. Caco-2 cells were cultivated in 96-well plates at 25000 cells/well, infected with SARS-CoV-2 d6-YFP at an MOI of 0.003 and treated with Compound 8, Example #4 or a combination of the drugs, starting at the respective 4 x EC50 concentrations of the single compounds. Viral replication was determined as 30 h post infection (p.i.) by quantitative fluorescence detection of virus-driven YFP expression in the fixed cells. Inhibitory profiles of viral replication measured through virus-encoded YFP reporter expression are presented in a bar chart of quadruplicate determinations (mean ±SD). The combinatorial drug assessment was calculated by using the CompuSyn algorithm as described m int. J. Mol. Sci. 2021;22:575.

Two representative experiments with Compound 8 are shown in Figure 1. Compound 8 shows synergistic antiviral effects on SARS-CoV-2 when combined with DHODH inhibitor Example #4. Same applies to Figure 2, where Compound 10 is used as alternative RORy/RORyt modulator, also showing a synergistic antiviral effect on SARS-CoV-2 when combined with DHODH inhibitor Example #4.

Example 203: Additive antiviral activity on SARS-CoV-2 with nucleoside analogue EIDD-1931

The additive potential of Compound 8 and Compound 10, respectively, together with the nucleoside analogue EIDD-1931 (CAS: 3258-02-4) was assessed.

The method of combinatorial drug assessment by a viral replication inhibition assay has been published in Pathogens 2021 jlO: 1076. Caco-2 cells were cultivated in 96-well plates at 25000 cells/well, infected with SARS-CoV-2 d6-YFP at an MOI of 0.003 and treated with Compound 8, EIDD-1931 or a combination of the drugs, starting at the respective 4 x EC50 concentrations of the single compounds. Viral replication was determined as 30 h post infection (p.i.) by quantitative fluorescence detection of virus-driven YFP expression in the fixed cells. Inhibitory profiles of viral replication measured through virus-encoded YFP reporter expression are presented in a bar chart of quadruplicate determinations (mean ±SD). The combinatorial drug assessment was calculated by using the CompuSyn algorithm as described in Int. J. Mol. Sci. 2021;22:575. Same applies with Compound 10 as an alternative RORy/RORyt modulator.

The representative experiments are shown in Figure 3. Compound 8 and Compound 10, respectively, show additive antiviral effects on SARS-CoV-2 when combined with nucleoside analogue EIDD-1931 (CAS: 3258-02-4). Example 204: Antiviral activity on SARS-CoV-2 variants of concern

Antiviral activity of selected compounds of the present invention against Delta and Omicron variants of concern were tested similar as for SARS-CoV-2 WT. Caco-2 cells were treated with serial dilutions of the indicated compound and then infected with SARS-CoV-2 reporter virus d6-YFP (WT) or clinical isolates of the Delta or Omicron variants. The number of infected cells was quantified by YFP expression for the WT or immunofluorescence staining with a dsRNA-specific antibody and a fluorophore-coupled secondary antibody and the respective EC50 concentration was calculated. The following results were obtained:

Claims

2. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a viral infection in a subject in need thereof according to claim 1, wherein the viral infection is caused by a coronavirus.

3. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof, for use in a method of treating a coronavirus infection in a subject in need thereof according to claim 2, wherein the coronavirus causes a SARS or MERS infection.

4. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of claims 1 to 3, wherein the coronavirus is SARS-CoV-2.

5. The RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof according to any one of claims 1 to 4, wherein the RORy/RORyt modulator is selected from the group consisting of:

6. The RORy/RORyt modulator for use in a method of treating a viral infection in a subject in need thereof according to any one of claims 1 to 4, wherein the RORy/RORyt modulator is selected from the group consisting of:

7. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of claims 1 to 6, wherein the administration of the RORy/RORyt modulator results in the reduction of the viral load in the subject.

8. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of claims 2 to 7, wherein the administration of the RORy/RORyt modulator is executed within the first 5 days after detection of the coronavirus infection or onset of symptoms.

9. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of claims 2 to 8, wherein the subject has had a known contact with a patient who has been diagnosed with a coronavirus, such as SARS-CoV-2 infection.

10. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of claims 2 to 8, wherein the subject begins administration of the RORy/RORyt modulator prior to being diagnosed with a coronavirus, especially SARS-CoV-2 infection.

11. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a coronavirus infection in a subject in need thereof according to any one of claims 2 to 8, wherein the administration of the RORy/RORyt modulator results in one or more clinical benefits.

12. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of claims 1 to 11, wherein the RORy/RORyt modulator is administered orally.

13. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of claims 1 to 12, wherein the RORy/RORyt modulator is administered for about 5 days to about 21 days.

14. The RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof for use in a method of treating a viral infection in a subject in need thereof according to any one of claims 1 to 13, wherein the RORy/RORyt modulator acts as a RORy/RORyt inverse agonist.

15. A pharmaceutical composition comprising the RORy/RORyt modulator or a pharmaceutically acceptable salt, a solvate, a solvate of a salt or a hydrate thereof according to any of claims 1 to 14 together with a pharmaceutically acceptable carrier or excipient.

16. A pharmaceutical composition of claim 15, further comprising one or more additional therapeutic agents selected from antiinflammatory agents, antiviral agents, immunosuppressive and/or immunomodulatory agents, steroids, non-steroidal antiinflammatory agents, antihistamines, analgesics and suitable mixtures thereof.

17. A pharmaceutical composition of claim 16, wherein the additional therapeutic agent is a DHODH inhibitor.