CN117321035A

CN117321035A - Deuterated DHODH inhibitors

Info

Publication number: CN117321035A
Application number: CN202280035549.7A
Authority: CN
Inventors: 克里斯蒂安·格格; 赫拉·科霍夫; 安德烈亚斯·穆勒; 丹尼尔·维特
Original assignee: Emnick AG
Current assignee: Emnick AG
Priority date: 2021-04-09
Filing date: 2022-04-08
Publication date: 2023-12-29

Abstract

The present invention relates to novel deuterated compounds of formula (I) and their use as pharmaceuticals.

Description

Deuterated DHODH inhibitors

Technical Field

The present disclosure relates to novel deuterated dihydroorotate dehydrogenase (DHODH) inhibitors, pharmaceutical formulations comprising them, processes for their preparation and their use as medicaments alone or in combination with one or more other agents for treating a variety of diseases in which inhibition of DHODH is desired.

Background

Vedoradine Mo Gai (IMU-838) is an alternative potent second generation dihydroorotate dehydrogenase (DHODH) oral immunomodulator developed for the treatment of a variety of inflammatory and inflammatory diseases including relapsing-remitting multiple sclerosis (rrMS):

vedoraforodipivoxil is a small molecule selective immunomodulator whose mechanism of action is to inhibit the intracellular metabolism of activated immune T cells and B cells by blocking DHODH enzyme. Inhibition of DHODH enzyme results in metabolic stress in metabolically activated lymphocytes, leading to a reduction of pro-inflammatory cytokines, followed by apoptosis of activated immune cells. Blocking DHODH enzyme activity has a selective effect on metabolically activated immune cells, on malignant cells and on virally infected cells. Thus DHODH inhibition does not therefore lead to general antiproliferative effects in other cells. IMU-838 is being developed as a second generation DHODH inhibitor with the aim of separating the desired immunomodulatory effects from unwanted side effects caused by off-target effects such as neutropenia, hair loss and diarrhea. Another benefit of DHODH inhibitors such as IMU-838 is their direct antiviral effect. Reactivation of latent viruses has been observed during long-term treatment with immunosuppressive drugs in the presence of the drug. This can lead to serious infections, such as progressive multifocal leukoencephalopathy, with fatal consequences.

PP-001 is another DHODH inhibitor within the same structural class and is currently being used in clinical trials to treat retinal diseases such as uveitis, diabetic macular edema, and retinal vein occlusion. In animal models, a high degree of effectiveness in treating ocular dryness and viral myometritis has been demonstrated.

There is a need to develop novel DHODH inhibitors. In particular, there is a need to develop DHODH inhibitors with improved pharmacokinetic properties. Covalent C-H bonds are weaker than in otherwise identical C-D bonds due to kinetic isotope effects. Breaking of C-H bonds is a common feature of drug metabolism, whereas breaking of similar C-D bonds may be more difficult, thus reducing the metabolic rate. Substitution of D for H in small molecules can lead to a significant reduction in metabolism, thus leading to beneficial changes in the biological effects of the drug. Substitutions may also have a downtoxic effect by reducing the formation of toxic metabolites (J.Med. Chem.2019; 62:5276). Deuteration analogs have the beneficial mechanism of action described, however, metabolism is expected to be slower and variability between patients to be smaller than non-deuterated counterpart pairs. It is widely recognized that differentiated pharmacokinetic profiles are likely to be such that they potentially improve efficacy, reduce dosing frequency, increase tolerability, reduce inter-patient drug metabolism variability, and reduce drug-drug interactions.

Prior Art

The unhydrogenated compounds of formula (I) are described in the following documents: WO2004/056746, WO2004/056747, WO2004/056797, WO2010/052027, WO2010/128050, WO2012/001148, WO2012/001151, WO2015/169944, WO2015/154820, WO2019/170848, WO2019/101888, WO2019/175396, and bioorg.med.chem.lett.2004;14:55, bioorg. Med. Chem. Lett.2005;15:4854, bioorg. Med. Chem. Lett.2006;16:267, and j.med.chem.2006;49:1239. Deuterated compounds of formula (I) have not been described.

Drawings

FIG. 1 depicts representative results of experiments in which example 9 was combined with a nucleotide analogue EIDD-1931 (CAS: 3258-02-4). The data show synergistic antiviral effects against SARS-CoV-2 at different doses.

Disclosure of Invention

The present invention relates to compounds of formula (I)

Or an enantiomer, diastereomer, tautomer, prodrug, solvate or pharmaceutically acceptable salt thereof, wherein

Ring a, ring B, ring C, X, R ¹ And R is ² As defined in claim 1,

provided that A, B, C, R ² And/or at least one hydrogen in X is replaced with deuterium, and the level of deuterium incorporation at each substituent designated as deuterium is at least 52.5%.

The compounds of the present invention have similar or better DHODH inhibitory activity than known DHODH inhibitors. Furthermore, the compounds of the present invention exhibit advantageous stability or pharmacokinetic properties when used as medicaments, as hydrogen is replaced by deuterium.

The invention therefore also relates to a pharmaceutical composition comprising a compound of formula (I) and at least one pharmaceutically acceptable carrier or excipient.

The invention also relates to compounds of formula (I) for the prophylaxis and/or treatment of diseases mediated by DHODH.

The present invention thus relates to the prevention and/or treatment of a disease, disorder, therapeutic indication or medical condition selected from the group consisting of rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, diseases caused by viral infections and pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthropathy. More specifically, the disease, disorder or therapeutic indication is selected from graft versus host and host versus graft response, rheumatoid arthritis, multiple sclerosis, myosallow lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, ulcerative colitis, crohn's disease, primary sclerosing cholangitis and psoriasis.

Detailed Description

The compound 2- ((3-fluoro-3 '-methoxy- [1,1' -biphenyl ] -4-yl) aminomethyl) cyclopent-1-ene-1-carboxylic acid, also known as vedofluradelomol, is an orally administered DHODH inhibitor. The calcium salt of vedoraforolamol is known as IMU-838.IMU-838 is currently in phase 2 clinical trials for the treatment of rrMS, ulcerative colitis, primary sclerosing cholangitis and COVID-19.

Compound 3- ((2,3,5,6-tetrafluoro-3 '- (trifluoromethoxy) - [1,1' -biphenyl ] -4-yl) aminomethyl) thiophene-2-carboxylic acid, also known as PP-001, is a topically applied DHODH inhibitor. PP-001 is currently in clinical trials for the treatment of keratoconjunctivitis and non-infectious uveitis.

In several clinical trials, the tolerability of vedoraforolamol, IMU-838 and PP-001 was generally good. Despite the potential beneficial activity of vedoraforadil, IMU-838 and PP-001, there remains a need for new compounds with improved Drug Metabolism and Pharmacokinetic (DMPK) properties in order to treat the above-mentioned diseases and conditions. Improved DMPK properties are likely to lead to positive changes in the safety, efficacy and tolerability of the compounds.

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to limit the invention to these embodiments. On the contrary, the invention is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. The present invention is not limited to the methods and materials described herein, but includes any methods and materials similar or equivalent to those described herein that can be used in the practice of the present invention. If one or more of the incorporated references, patents or similar materials are different from or contradict the present application, including but not limited to defined terms, use of terms, described techniques, etc., the present application controls.

The desired properties of DHODH inhibitors can be obtained with compounds that conform to the structural pattern represented by formula (I) or enantiomers, diastereomers, tautomers, prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein the method comprises the steps of

A is selected from the group consisting of 5 membered heteroaryl groups having one or more hydrogen atoms optionally replaced with deuterium, cyclopentenyl and heterocycloalkenyl,

said A is unsubstituted or is substituted with 1 to 5 groups independently selected from halogen, CN, NO ₂ Oxo, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 Alkyl, CO ₂ H and SO ₃ A substituent for H, one or more hydrogen atoms in the alkyl group optionally being replaced by deuterium;

b is selected from the group consisting of 5-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, 6-or 10-membered aryl, and 5-10 membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O and S,

wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, -CN, -NO ₂ Oxo, C _1-4 -alkyl, C _0-6 -alkylene-OR ²⁷ 、C _0-6 Alkylene- (3-6 membered cycloalkyl) radicals, C _0-6 Alkylene- (3-6 membered heterocycloalkyl), C _0-6 -alkylene-S (=o) _n (＝NR ²⁹ ) _m R ²⁷ 、C _0-6 -alkylene-NR ²⁷ S(＝O) _x (＝NR ²⁹ ) _y R ²⁷ 、C _0-6 -alkylene-S (=o) _x (＝NR ²⁹ ) _y NR ²⁷ R ²⁸ 、C _0-6 -alkylene-NR ²⁷ S(＝O) _x (＝NR ²⁹ ) _y NR ²⁷ R ²⁸ 、C _0-6 -alkylene-CO ₂ R ²⁷ 、C _0-6 -alkylene-O-COR ²⁷ 、C _0-6 -alkylene-CONR ²⁷ R ²⁸ 、C _0-6 -alkylene-NR ²⁷ -COR ²⁷ 、C _0-6 -alkylene-NR ²⁷ -CONR ²⁷ R ²⁸ 、C _0-6 -alkylene-O-CONR ²⁷ R ²⁸ 、C _0-6 -alkylene-NR ²⁷ -CO ₂ R ²⁷ 、C _0-6 -alkylene-NR ²⁷ R ²⁸ ，

Wherein alkyl, alkylene, 3-6 membered heterocycloalkyl, and 3-6 membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, -CN, oxo, -OH, C _1-4 -alkyl, halo-C _1-4 -alkyl, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group;

wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N,

wherein the additional ring is optionally substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, -CN, oxo, -OH, C _1-4 -alkyl, halo-C _1-4 -alkyl, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group, which is a group,

wherein the residue on ring B-NR ² In 1,4-orientation relative to ring C,

ring B or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium;

c is selected from the group consisting of 5-10 membered heterocycloalkyl, 4-10 membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, 6-or 10-membered aryl, and 5-10 membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O and S,

Wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, -CN, -NO ₂ Oxo, C _1-4 -alkyl, C _0-6 -alkylene-OR ³¹ 、C _0-6 Alkylene- (3-6 membered cycloalkyl) radicals, C _0-6 Alkylene- (3-6 membered heterocycloalkyl), C _0-6 -alkylene-S (=o) _n (＝NR ³³ ) _m R ³¹ 、C _0-6 -alkylene-NR ³¹ S(＝O) _x (＝NR ³³ ) _y R ³¹ 、C _0-6 -alkylene-S (=o) _x (＝NR ³³ ) _y NR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ S(＝O) _x (＝NR ³³ ) _y NR ³¹ R ³² 、C _0-6 -alkylene-CO ₂ R ³¹ 、C _0-6 -alkylene-O-COR ³¹ 、C _0-6 -alkylene-CONR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ -COR ³¹ 、C _0-6 -alkylene-NR ³¹ -CONR ³¹ R ³² 、C _0-6 -alkylene-O-CONR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ -CO ₂ R ³¹ 、C _0-6 -alkylene-NR ³¹ R ³² ，

Ring C or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium;

x is selected from H, D, halogen, -CN, -NO ₂ 、C _1-6 -alkyl, -O-C _1-6 -alkyl, O-halo-C _1-6 -alkyl, C _0-6 -alkylene-OR ⁴¹ 、C _0-6 Alkylene- (3-6 membered cycloalkyl) radicals, C _0-6 Alkylene- (3-6 membered heterocycloalkyl), C _0-6 -alkylene-S (=o) _n (＝NR ⁴³ ) _m R ⁴¹ 、C _0-6 -alkylene-NR ⁴¹ S(＝O) _x (＝NR ⁴³ ) _y R ⁴¹ 、C _0-6 -alkylene-S (=o) _x (＝NR ⁴³ ) _y NR ⁴¹ R ⁴² 、C _0-6 -alkylene-NR ⁴¹ S(＝O) _x (＝NR ⁴³ ) _y NR ⁴¹ R ⁴² 、C _0-6 -alkylene-CO ₂ R ⁴¹ 、C _0-6 -alkylene-O-COR ⁴¹ 、C _0-6 -alkylene-CONR ⁴¹ R ⁴² 、C _0-6 -alkylene-NR ⁴¹ -COR ⁴¹ 、C _0-6 -alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² 、C _0-6 -alkylene-O-CONR ⁴¹ R ⁴² 、C _0-6 -alkylene-NR ⁴¹ -CO ₂ R ⁴¹ 、C _0-6 -alkylene-NR ⁴¹ R ⁴² Wherein the heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms independently selected from N, O or S,

wherein alkyl, alkylene, cycloalkyl and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, -CN, oxo, -OH, C _1-4 -alkyl, halo-C _1-4 -alkyl, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group, which is a group,

x or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium;

R ¹ selected from H and D;

R ² selected from H and C _1-6 -an alkyl group, which is a group,

wherein the alkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 Alkyl, wherein the heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O or S,

R ² or a substituent thereof with one or more hydrogen atoms optionally replaced by deuterium;

R ²⁷ 、R ²⁸ 、R ³¹ 、R ³² 、R ⁴¹ 、R ⁴² independently selectFrom H, C _1-6 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl,

wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 Alkyl, wherein the heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O or S,

R ²⁷ and/or R ²⁸ And/or R ³¹ And/or R ³² And/or R ⁴¹ And/or R ⁴² Or substituents thereof, respectively, have one or more hydrogen atoms optionally replaced by deuterium;

or R is ²⁷ And R is ²⁸ 、R ³¹ And R is ³² 、R ⁴¹ And R is ⁴² A 3-6 membered ring containing a carbon atom and optionally containing 1 or 2 heteroatoms selected from O, S or N, respectively, is completed when taken together with the nitrogen to which they are attached; and is also provided with

Wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group, which is a group,

R ²⁹ 、R ³³ 、R ⁴³ independently selected from H, -CN, -NO ₂ 、C _1-6 -alkyl, -CO-O-C _1-6 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl,

R ²⁹ and/or R ³³ And/or R ⁴³ Or substituents thereof, respectively, have one or more hydrogen atoms optionally replaced by deuterium;

n, m, x, y are independently selected from 0 to 2;

provided that the sum of the integers m and n of the residuum linked to one sulfur atom is independently selected from 0 to 2;

provided that the sum of the residues attached to one sulfur atom, x and y, are independently selected from 1 or 2;

Provided that A, B, C, R ² 、R ²⁷ 、R ²⁸ 、R ²⁹ 、R ³¹ 、R ³² 、R ³³ 、R ⁴¹ 、R ⁴² 、R ⁴³ And/or at least one hydrogen in X is replaced with deuterium;

provided that the deuterium incorporation level at each substituent designated as deuterium is at least 52.5%.

In a more specific embodiment, the compound is represented by formula (I), a solvate or pharmaceutically acceptable salt thereof, wherein

R ¹ Is H and R ² Is H.

In a more particular embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), whereinSelected from->

In a particular embodiment analogous to one in combination with any of the above or below embodiments, the compound is represented by formula (I), wherein

-NR ² B is selected from

C is phenyl, pyrazolone or thiotezate,

wherein phenyl, pyrazoloyl, or tehizayl is unsubstituted or substituted with 1 to 4 substituents independently selected from D and F;

x is selected from D, F, cl, -CN, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl, O-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium.

In a more particular embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), wherein Selected from the group consisting of

In a more particular embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), whereinSelected from the group consisting of

In a more particular embodiment in combination with any of the above or below embodiments, the compound is represented by formula (I), wherein

R ¹ Is H and R ² Is H;

selected from->

-NR ² B is selected from

Selected from->

In a most particular embodiment, the compound is selected from

Or a solvate or pharmaceutically acceptable salt thereof.

The invention also provides a compound of the invention for use as a medicament.

Also provided are compounds of the invention for use in the prevention and/or treatment of diseases, disorders, therapeutic indications or medical conditions suitable for treatment with DHODH inhibitors.

Also provided are compounds of the invention for use in the prevention and/or treatment of DHODH mediated diseases selected from the group consisting of rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, diseases caused by viral infections and pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation, or arthropathy.

More particularly, the present invention relates to a compound of the present invention for use wherein the disease, disorder or therapeutic indication is selected from graft versus host and host versus graft response, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, influenza, ulcerative colitis, crohn's disease, primary sclerosing cholangitis and psoriasis.

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

Also provided is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient, and further comprising one or more additional therapeutic agents selected from the group consisting of anti-viral agents, anti-inflammatory agents, immunosuppressants and/or immunomodulators, compounds of the castanosperms, non-castanosperms, antihistamines, analgesics, and suitable mixtures thereof.

Furthermore, the desired properties of DHODH inhibitors can be obtained with compounds conforming to the structural pattern represented by formula (I) or enantiomers, diastereomers, tautomers, prodrugs, solvates or pharmaceutically acceptable salts thereof:

wherein the method comprises the steps of

R ¹ And R is ² Independently selected from H and D;

R ³ 、R ⁴ 、R ⁵ and R is ⁶ Independently selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium;

R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Independently selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium;

X is selected from H, D, OH, OD, S (=O) _y R ¹¹ And OR ¹¹ ；

R ¹¹ Selected from C _1-4 -alkyl, C _3-4 -cycloalkyl and fluoro-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium;

y is 0 to 2;

selected from the group consisting of 5 membered heteroaryl groups, cyclopentenyl groups and heterocycloalkenyl groups having one or more hydrogen atoms optionally replaced by deuterium,

provided that R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ At least one hydrogen of X and/or A is replaced byDeuterium substitution.

In one embodiment, the compound is represented by formula (I) or a prodrug, pharmaceutically acceptable salt or solvate thereof, wherein

R ¹ And R is ² Independently selected from H and D;

R ³ 、R ⁴ 、R ⁵ and R is ⁶ Independently selected from H, D, F and Cl;

R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Independently selected from H, D and F;

x is selected from H, D, OH, OD and OR ¹¹ ；

R ¹¹ Selected from C _1-4 -alkyl and fluoro-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium;

selected from->Wherein one or more hydrogen atoms are optionally replaced with deuterium;

provided that R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ And/or at least one hydrogen in a is replaced with deuterium.

In a particular embodiment, the compound is represented by formula (I) or a prodrug, pharmaceutically acceptable salt or solvate thereof, wherein

R ³ Is F;

R ⁴ 、R ⁵ and R is ⁶ Independently selected from H, D and F;

R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Independently selected from H and D;

x is selected from OH, OD and OR ¹¹ ；

R ¹¹ Selected from CH ₃ 、CD ₃ 、CHF ₂ 、CDF ₂ And CF (compact F) ₃ ；

Is->

R ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ And R is ²⁶ Independently selected from H and D;

provided that R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ 、R ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ And/or R ²⁶ Is replaced with deuterium.

In a more specific embodiment, the compound is represented by formula (I) or a prodrug, pharmaceutically acceptable salt or solvate thereof, wherein

R ⁴ 、R ⁵ And R is ⁶ Independently selected from H and D;

x is OR ¹¹ ；

R ¹¹ Selected from CH ₃ And CD (compact disc) ₃ ；

In a more particular embodiment in combination with any of the above or below embodiments, R ¹¹ Is a CD ₃ 。

In a more specific embodiment, the compound is selected from

/>

Or a solvate or pharmaceutically acceptable salt thereof.

In a most particular embodiment, the compound is selected from

Or a solvate or pharmaceutically acceptable salt thereof.

In a similar particular embodiment, the compound is represented by formula (I) or a prodrug, pharmaceutically acceptable salt or solvate thereof, wherein

R ¹ And R is ² Independently selected from H and D;

R ³ 、R ⁴ 、R ⁵ and R is ⁶ Independently selected from H, D, F and Cl;

R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Independently selected from H, D and F;

x is OR ¹¹ ；

is->Wherein one or more hydrogen atoms are optionally replaced with deuterium;

In a similar most specific embodiment, the compound is

Or a solvate or pharmaceutically acceptable salt thereof.

More particularly, the present invention relates to a compound of the present invention for use wherein the disease, disorder or therapeutic indication is selected from graft versus host and host versus graft response, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, ulcerative colitis, crohn's disease, primary sclerosing cholangitis and psoriasis.

Also provided is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient, and further comprising one or more additional therapeutic agents selected from the group consisting of anti-inflammatory agents, immunosuppressants and/or immunomodulators, castano-anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

In certain embodiments, the invention relates to a compound of formula (I) as set forth below:

1. a compound of formula (I):

R ¹ And R is ² Independently selected from H and D;

x is selected from H, D, OH, OD, S (=O) _y R ¹¹ And OR ¹¹ ；

y is 0 to 2;

provided that R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ 、R ¹¹ At least one hydrogen in X and/or a is replaced with deuterium.

2. The compound of formula (I) according to claim 1, or a prodrug, pharmaceutically acceptable salt or solvate thereof, wherein

R ¹ And R is ² Independently selected from H and D;

R ³ 、R ⁴ 、R ⁵ and R is ⁶ Independently selected from H, D, F and Cl;

R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Independently selected from H, D and F;

x is selected from H, D, OH, OD and OR ¹¹ ；

3. The compound of formula (I) according to claim 2, or a prodrug, pharmaceutically acceptable salt or solvate thereof, wherein

R ³ Is F;

R ⁴ 、R ⁵ and R is ⁶ Independently selected from H, D and F;

R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Independently selected from H and D;

x is selected from OH, OD and OR ¹¹ ；

Is->

4. The compound of formula (I) according to claim 3, or a prodrug, pharmaceutically acceptable salt or solvate thereof, wherein

R ⁴ 、R ⁵ And R is ⁶ Independently selected from H and D;

x is OR ¹¹ ；

R ¹¹ Selected from CH ₃ And CD (compact disc) ₃ ；

5. The compound according to item 1 to 4, wherein R ¹¹ Is a CD ₃ 。

6. A compound according to any one of the preceding claims selected from

Or a solvate or pharmaceutically acceptable salt thereof.

7. The compound of formula (I) or a prodrug, pharmaceutically acceptable salt or solvate thereof according to item 1 or 2, wherein

R ¹ And R is ² Independently selected from H and D;

R ³ 、R ⁴ 、R ⁵ and R is ⁶ Independently selected from H, D, F and Cl;

R ⁷ 、R ⁸ 、R ⁹ and R is ¹⁰ Independently selected from H, D and F;

x is OR ¹¹ ；

is->Wherein one or more hydrogen atoms are optionally replaced with deuterium;

8. The compound according to any one of the preceding claims, which is

Or a solvate or pharmaceutically acceptable salt thereof.

9. A compound according to any one of the preceding claims for use as a medicament.

10. The compound according to any one of items 1 to 9 for use in the prevention and/or treatment of a disease, disorder, therapeutic indication or medical condition suitable for treatment with a DHODH inhibitor.

11. The compound for use according to item 10, wherein the disease, disorder, therapeutic indication or medical condition is selected from the group consisting of rheumatism, acute immune disorder, autoimmune disease, disease caused by malignant cell proliferation, inflammatory disease, disease caused by protozoal infection in humans and animals, disease caused by viral infection and pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthrosis.

12. A compound for use according to item 11, wherein the disease, disorder or therapeutic indication is selected from graft versus host and host versus graft response, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, ulcerative colitis, crohn's disease, primary sclerosing cholangitis and psoriasis.

13. A pharmaceutical composition comprising a compound according to any one of items 1 to 8 and a pharmaceutically acceptable carrier or excipient.

14. The pharmaceutical composition of claim 13, further comprising one or more additional therapeutic agents selected from the group consisting of anti-inflammatory agents, immunosuppressants and/or immunomodulators, compounds of the family, non-family anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

15. A compound of formula (I):

Said A is unsubstituted or is substituted with 1 to 5 groups independently selected from halogen, CN,NO ₂ Oxo, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 Alkyl, CO ₂ H and SO ₃ A substituent for H, one or more hydrogen atoms in the alkyl group optionally being replaced by deuterium;

Wherein alkyl, alkylene, 3-6 membered heterocycloalkyl, and 3-6 membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, -CN, oxo, -OH, C _1-4 -alkyl, halo-C _1-4 Alkyl radicalsO-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group;

wherein residue-NR on ring B ² In 1,4-orientation relative to ring C,

and wherein optionally two adjacent substituents in the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N,

R ¹ selected from H and D;

R ² selected from H and C _1-6 -an alkyl group, which is a group,

R ²⁷ 、R ²⁸ 、R ³¹ 、R ³² 、R ⁴¹ 、R ⁴² independently selected from H, C _1-6 Alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl,

Wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered cycloalkyl), 3-6 memberedHeterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 Alkyl, wherein the heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O or S,

n, m, x, y are independently selected from 0 to 2;

16. The compound of formula (I) according to claim 15, wherein

R ¹ Is H and R ² Is H.

17. The compound of formula (I) according to item 15 or 16, whereinSelected from the group consisting of

18. The compound of formula (I) according to any one of items 15 to 17, wherein-NR ² B is selected from

19. The compound of formula (I) according to any one of items 15 to 18, wherein

C is phenyl, pyrazolone or thiotezate,

20. The compound of formula (I) according to any one of items 15 to 19, whereinSelected from the group consisting of

21. The compound of formula (I) according to any one of items 15 to 20, whereinSelected from->

22. The compound of formula (I) according to any one of items 15 to 21, wherein R ¹ Is H and R ² Is H;

selected from->

-NR ² B is selected from />

Selected from->

23. A compound of formula (I) as described in any one of items 15 to 22, selected from

/>

Or a solvate or pharmaceutically acceptable salt thereof.

24. The compound according to any one of items 15 to 23 for use as a medicament.

25. A compound according to any one of claims 15 to 24 for use in the prevention and/or treatment of a disease, disorder, therapeutic indication or medical condition suitable for treatment with a DHODH inhibitor.

26. A compound for use according to item 25, wherein the disease, disorder, therapeutic indication or medical condition is selected from the group consisting of rheumatism, acute immune disorder, autoimmune disease, disease caused by malignant cell proliferation, inflammatory disease, disease caused by protozoal infection in humans and animals, disease caused by viral infection and pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthrosis.

27. A compound for use according to item 26, wherein the disease, disorder or therapeutic indication is selected from graft versus host and host versus graft response, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, influenza, ulcerative colitis, crohn's disease, primary sclerosing cholangitis and psoriasis.

28. A pharmaceutical composition comprising a compound according to any one of items 15 to 23 and a pharmaceutically acceptable carrier or excipient.

29. The pharmaceutical composition of claim 28, further comprising one or more additional therapeutic agents selected from the group consisting of antiviral agents, anti-inflammatory agents, immunosuppressants and/or immunomodulators, compounds of the family, non-family anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.

30. The pharmaceutical composition of claim 29, further comprising an additional therapeutic agent, monolavir.

In particular embodiments, as used herein, wherein when R ¹ And R is ² When any one of them is deuterium, R is designated as deuterium ¹ And R is ² Deuterium incorporation levels at each of (a) is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%; when R is ³ 、R ⁴ 、R ⁵ And R is ⁶ When any one of them is deuterium, R is designated as deuterium ³ 、R ⁴ 、R ⁵ And R is ⁶ Deuterium incorporation levels at each of (a) is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%; when R is ⁷ 、R ⁸ 、R ⁹ And R is ¹⁰ When any one of them is deuterium, R ⁷ 、R ⁸ 、R ⁹ And R is ¹⁰ Deuterium incorporation levels at each of (a) is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98%, or at least 99%; when R is ¹¹ Any residue of (B) containing one or more residuesWhen deuterium is plural, R ¹¹ Deuterium incorporation levels at each position of at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99%; when any of the residues in ring a contains one or more deuterium, the deuterium incorporation level at each position in ring a is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99%; when R is ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ And R is ²⁶ When any one of them is deuterium, R ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ And R is ²⁶ Deuterium incorporation levels at each of (a) is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, at least 98% or at least 99%.

Quantitative analysis of particularly deuterated compounds can be accomplished by a number of conventional methods such as mass spectrometry (peak area), or by signal with internal standards or other non-deuterated compounds ¹ Quantification of the residual residues of the specific deuterated sites compared to the H signal ¹ H-NMR signal.

In certain embodiments, the incorporation level of deuterium at each substituent designated as deuterium is at least 52.5%. More particularly, deuterium incorporation levels at each substituent designated as deuterium are at least 90%. Even more particularly, the deuterium incorporation level at each substituent designated as deuterium is at least 95%. Most particularly, the incorporation level of deuterium at each substituent designated as deuterium is at least 98%.

In particular embodiments, as used herein, ring a represents a 5 membered heteroaryl, cyclopentenyl and heterocycloalkenyl group having one or more hydrogen atoms optionally replaced with deuterium, said ring a being unsubstituted or substituted with 1 to 5 groups independently selected from halogen, CN, NO ₂ Oxo, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 Alkyl, CO ₂ H and SO ₃ The substituent of H is substituted, and one or more hydrogen atoms in the alkyl group are optionally replaced by deuterium. More particularly, ring A representsUnsubstituted 5 membered heteroaryl, cyclopentenyl and heterocycloalkenyl groups having one or more hydrogen atoms optionally replaced with deuterium. More particularly, the ringRepresentation->Wherein one or more hydrogen atoms are optionally replaced by deuterium.

More particularly, ring A representsWherein one or more hydrogen atoms are optionally replaced by deuterium. Even more particularly, ring A represents +.>Wherein R is ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ And R is ²⁶ Independently selected from H and D. Most particularly, ring A represents +.>Wherein R is ²¹ 、R ²² 、R ²³ 、R ²⁴ 、R ²⁵ And R is ²⁶ Is H.

In particular embodiments, as used herein, ring a represents a 5 membered heteroaryl, cyclopentenyl and heterocycloalkenyl group having one or more hydrogen atoms optionally replaced with deuterium, said ring a being unsubstituted or substituted with 1 to 5 groups independently selected from halogen, CN, NO ₂ Oxo, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 Alkyl, CO ₂ H and SO ₃ The substituent of H is substituted, and one or more hydrogen atoms in the alkyl group are optionally replaced by deuterium. More particularly, ring a represents an unsubstituted 5 membered heteroaryl, cyclopentenyl and heterocycloalkenyl group having one or more hydrogen atoms optionally replaced by fluorine or deuterium. More particularly, the ringRepresentation->Most particularly, ring A represents

In a particular embodiment of the invention, R ¹ Prodrugs independently selected from H and D or acid moieties. More particularly, R ¹ Is H.

In a particular embodiment of the invention, R ² Selected from H and C _1-6 -an alkyl group, said alkyl group being unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 -alkyl, wherein heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, and wherein R ² Or a substituent thereof having one or more hydrogen atoms optionally replaced with deuterium. More particularly, R ² Is H, D or methyl.

In a particular embodiment of the invention, R ² Independently selected from H and D. More particularly, R ² Is H.

In a particular embodiment of the invention, R ¹ Is H and R ² Is H.

In a particular embodiment of the invention, R ³ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ³ Selected from H, D, F, cl, CH ₃ 、CHF ₂ 、CF ₃ 、CD ₃ 、OCH ₃ 、OCD ₃ 、OCHF ₂ And OCF (optical fiber) ₃ . More particularly, R ³ Selected from H, D, F and Cl. Most particularly, R ³ Is F.

In a particular embodiment of the invention, R ⁴ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ⁴ Selected from H, D, F, cl, CH ₃ 、CHF ₂ 、CF ₃ 、CD ₃ 、OCH ₃ 、OCD ₃ 、OCHF ₂ And OCF (optical fiber) ₃ . More particularly, R ⁴ Selected from H, D and F. Most particularly, R ⁴ Is H.

In a particular embodiment of the invention, R ⁵ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ⁵ Selected from H, D, F, cl, CH ₃ 、CHF ₂ 、CF ₃ 、CD ₃ 、OCH ₃ 、OCD ₃ 、OCHF ₂ And OCF (optical fiber) ₃ . More particularly, R ⁵ Selected from H, D and F. Most particularly, R ⁵ Is H.

In a particular embodiment of the invention, R ⁶ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ⁶ Selected from H, D, F, cl, CH ₃ 、CHF ₂ 、CF ₃ 、CD ₃ 、OCH ₃ 、OCD ₃ 、OCHF ₂ And OCF (optical fiber) ₃ . More particularly, R ⁶ Selected from H, D and F. Most particularly, R ⁶ Is H.

In a particular embodiment of the present invention,selected from the group consisting of

Wherein one or more hydrogen atoms are optionally replaced by deuterium. More particularly, it is possible to provide,selected from the group consisting ofMost particularly, the->Is->

In a particular embodiment of the invention, ring B is selected from 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, 6-or 10 membered aryl, and 5-10 membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O and S, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, -CN, -NO ₂ Oxo, C _1-4 -alkyl, C _0-6 -alkylene-OR ²⁷ 、C _0-6 Alkylene- (3-6 membered cycloalkyl) radicals, C _0-6 Alkylene- (3-6 membered heterocycloalkyl), C _0-6 -alkylene-S (=o) _n (＝NR ²⁹ ) _m R ²⁷ 、C _0-6 -alkylene-NR ²⁷ S(＝O) _x (＝NR ²⁹ ) _y R ²⁷ 、C _0-6 -alkylene-S (=o) _x (＝NR ²⁹ ) _y NR ²⁷ R ²⁸ 、C _0-6 -alkylene-NR ²⁷ S(＝O) _x (＝NR ²⁹ ) _y NR ²⁷ R ²⁸ 、C _0-6 -alkylene-CO ₂ R ²⁷ 、C _0-6 Alkylene groupradical-O-COR ²⁷ 、C _0-6 -alkylene-CONR ²⁷ R ²⁸ 、C _0-6 -alkylene-NR ²⁷ -COR ²⁷ 、C _0-6 -alkylene-NR ²⁷ -CONR ²⁷ R ²⁸ 、C _0-6 -alkylene-O-CONR ²⁷ R ²⁸ 、C _0-6 -alkylene-NR ²⁷ -CO ₂ R ²⁷ 、C _0-6 -alkylene-NR ²⁷ R ²⁸ Wherein alkyl, alkylene, 3-6 membered heterocycloalkyl, and 3-6 membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, -CN, oxo, -OH, C _1-4 -alkyl, halo-C _1-4 -alkyl, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group;

wherein optionally, two adjacent substituents in the aryl or heteroaryl moiety form a 5-8 membered partially unsaturated ring optionally containing 1 to 3 heteroatoms independently selected from O, S or N, wherein the additional ring is optionally substituted with 1 to 4 substituents independently selected from the following: halogen, -CN, oxo, -OH, C _1-4 -alkyl, halo-C _1-4 -alkyl, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group, which is a group,

wherein residue-NR on ring B ² In 1,4-orientation relative to ring C, and ring B or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium.

In a more specific embodiment of the invention, -NR ² B is selected from

Wherein one or more hydrogen atoms are optionally replaced by deuterium.

In a more specific embodiment of the invention, -NR ² B is selected from

In an even more specific embodiment of the invention, -NR ² B is selected from

In the most specific embodiment of the invention, -NR ² B is selected from

In a particular embodiment of the invention, R ⁷ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ⁷ Selected from H and D. Most particularly, R ⁷ Is H.

In a particular embodiment of the invention, R ⁸ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ⁸ Selected from H and D. Most particularly, R ⁸ Is H.

In a particular embodiment of the invention, R ⁹ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ⁹ Selected from H and D. Most particularly, R ⁹ Is H.

In a particular embodiment of the invention, R ¹⁰ Selected from H, D, halogen, CN, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl and O-fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ¹⁰ Selected from H and D. Most particularly, it is the most preferred that,R ¹⁰ is H.

In a particular embodiment of the present invention,is->Wherein one or more hydrogen atoms are optionally replaced by deuterium. More particularly, the->Selected from->Most particularly, the->Is that

In a particular embodiment of the invention, X is selected from H, D, OH, OD, S (=o) _y R ¹¹ And OR ¹¹ . More particularly, X is selected from OH and OR ¹¹ . Most particularly, X is OR ¹¹ 。

In a particular embodiment of the invention, R ¹¹ Selected from C _1-4 -alkyl, C _3-4 -cycloalkyl and fluoro-C _1-4 -alkyl groups, in which one or more hydrogen atoms are optionally replaced by deuterium. More particularly, R ¹¹ Selected from CH ₃ 、CD ₃ 、CHF ₂ 、CDF ₂ And CF (compact F) ₃ . Most particularly, R ¹¹ Is a CD ₃ 。

In a particular embodiment of the present invention,selected from the group consisting ofMost particularly, the->Is that

In a particular embodiment of the invention, ring C is selected from 5-10 membered cycloalkyl, 4-10 membered heterocycloalkyl containing 1 to 4 heteroatoms independently selected from N, O and S, 6-or 10 membered aryl, and 5-10 membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O and S, wherein said cycloalkyl, heterocycloalkyl, aryl and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, -CN, -NO ₂ Oxo, C _1-4 -alkyl, C _0-6 -alkylene-OR ³¹ 、C _0-6 Alkylene- (3-6 membered cycloalkyl) radicals, C _0-6 Alkylene- (3-6 membered heterocycloalkyl), C _0-6 -alkylene-S (=o) _n (＝NR ³³ ) _m R ³¹ 、C _0-6 -alkylene-NR ³¹ S(＝O) _x (＝NR ³³ ) _y R ³¹ 、C _0-6 -alkylene-S (=o) _x (＝NR ³³ ) _y NR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ S(＝O) _x (＝NR ³³ ) _y NR ³¹ R ³² 、C _0-6 -alkylene-CO ₂ R ³¹ 、C _0-6 -alkylene-O-COR ³¹ 、C _0-6 -alkylene-CONR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ -COR ³¹ 、C _0-6 -alkylene-NR ³¹ -CONR ³¹ R ³² 、C _0-6 -alkylene-O-CONR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ -CO ₂ R ³¹ 、C _0-6 -alkylene-NR ³¹ R ³² Wherein alkyl, alkylene, 3-6 membered heterocycloalkyl, and 3-6 membered heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, -CN, oxo, -OH, C _1-4 Alkyl, halogen-C _1-4 -alkyl, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group;

and ring C or a substituent thereof has one or more hydrogen atoms optionally replaced by deuterium;

in a more particular embodiment of the invention, ring C is phenyl, pyrazolo, or tebuconazole, wherein phenyl, pyrazolo, or tebuconazole is unsubstituted or substituted with 1 to 4 substituents independently selected from D and F; and X is selected from D, F, cl, -CN, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl, O-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium.

In a more specific embodiment of the invention, ring C is selected from

In a more specific embodiment of the invention, ring C is selected fromMore particularly, ring C is +.>

In a particular embodiment of the invention, X is selected from H, D, halogen, -CN, -NO ₂ 、C _1-6 -alkyl, -O-C _1-6 -alkyl, O-halo-C _1-6 -alkyl, C _0-6 -alkylene-OR ⁴¹ 、C _0-6 Alkylene- (3-6 membered cycloalkyl) radicals, C _0-6 Alkylene- (3-6 membered heterocycloalkyl), C _0-6 -alkylene-S (=o) _n (＝NR ⁴³ ) _m R ⁴¹ 、C _0-6 -alkylene-NR ⁴¹ S(＝O) _x (＝NR ⁴³ ) _y R ⁴¹ 、C _0-6 -alkylene-S (=o) _x (＝NR ⁴³ ) _y NR ⁴¹ R ⁴² 、C _0-6 -alkylene-NR ⁴¹ S(＝O) _x (＝NR ⁴³ ) _y NR ⁴¹ R ⁴² 、C _0-6 -alkylene-CO ₂ R ⁴¹ 、C _0-6 -alkylene-O-COR ⁴¹ 、C _0-6 -alkylene-CONR ⁴¹ R ⁴² 、C _0-6 -alkylene-NR ⁴¹ -COR ⁴¹ 、C _0-6 -alkylene-NR ⁴¹ -CONR ⁴¹ R ⁴² 、C _0-6 -alkylene-O-CONR ⁴¹ R ⁴² 、C _0-6 -alkylene-NR ⁴¹ -CO ₂ R ⁴¹ 、C _0-6 -alkylene-NR ⁴¹ R ⁴² Wherein the heterocycloalkyl comprises 1, 2, 3, or 4 heteroatoms independently selected from N, O or S, wherein alkyl, alkylene, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 6 substituents independently selected from the group consisting of: halogen, -CN, oxo, -OH, C _1-4 -alkyl, halo-C _1-4 -alkyl, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group, which is a group,

and X or a substituent thereof has one or more hydrogen atoms optionally replaced with deuterium.

In a more specific embodiment of the invention, X is selected from D, F, cl, -CN, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl, O-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium.

In a more specific embodiment of the invention, X is selected from D, F, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl, O-fluoro-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium.

In a more specific embodiment of the present invention, X is selected from D, F, CD ₃ 、CD ₂ CD ₃ 、OH、OCD ₃ 、OCD ₂ CD ₃ 、O(CD ₂ ) ₃ CD ₃ 、OCF ₃ 、OCDF ₂ And OCHF ₂ . Most particularly, X is OCD ₃ 。

In certain embodiments of the invention, ring C is phenyl, pyrazolo, or tebuconazole, wherein phenyl, pyrazolo, or tebuconazole is unsubstituted or substituted with 1 to 4 substituents independently selected from D and F; and X is selected from D, F, cl, -CN, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl, O-C _1-4 -alkyl groups in which one or more hydrogen atoms are optionally replaced by deuterium.

In a particular embodiment of the present invention,selected from the group consisting of Most particularly, the->Selected from the group consisting of

Most particularly, it is the most preferred that,is->

/>

In a more specific embodiment of the invention,selected from the group consisting of

/> More particularly, it is possible to provide, Selected from the group consisting of

More particularly, it is possible to provide,is that

In a particular embodiment of the invention, R ²⁷ 、R ²⁸ 、R ³¹ 、R ³² 、R ⁴¹ 、R ⁴² Independently selected from H, C _1-6 -alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 -alkyl, wherein heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, and R ²⁷ And/or R ²⁸ And/or R ³¹ And/or R ³² And/or R ⁴¹ And/or R ⁴² Or substituents thereof, respectively, have one or more hydrogen atoms optionally replaced by deuterium;

or R is ²⁷ And R is ²⁸ 、R ³¹ And R is ³² 、R ⁴¹ And R is ⁴² A 3-6 membered ring containing a carbon atom and optionally containing 1 or 2 heteroatoms selected from O, S or N, respectively, is completed when taken together with the nitrogen to which they are attached; and wherein the ring is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 -an alkyl group; r is R ²⁷ And/or R ²⁸ And/or R ³¹ And/or R ³² And/or R ⁴¹ And/or R ⁴² Or substituents thereof, respectively, have one or more hydrogen atoms optionally replaced by deuterium.

In a particular embodiment of the invention, R ²⁷ 、R ²⁸ 、R ³¹ 、R ³² 、R ⁴¹ 、R ⁴² Independently selected from H, CH ₃ And CD (compact disc) ₃ 。

In a particular embodiment of the invention, R ²⁹ 、R ³³ 、R ⁴³ Independently selected from H, -CN, -NO ₂ 、C _1-6 -alkyl, -CO-O-C _1-6 -alkyl, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein alkyl, cycloalkyl or heterocycloalkyl is unsubstituted or substituted with 1 to 3 substituents independently selected from the group consisting of: halogen, -CN, C _1-4 -alkyl, halo-C _1-4 -alkyl, 3-6 membered cycloalkyl, halo- (3-6 membered heterocycloalkyl), 3-6 membered heterocycloalkyl, halo- (3-6 membered heterocycloalkyl), -OH, oxo, -O-C _1-4 -alkyl and-O-halo-C _1-4 -alkyl, wherein heterocycloalkyl comprises 1, 2, 3 or 4 heteroatoms independently selected from N, O or S; r is R ²⁹ And/or R ³³ And/or R ⁴³ Or substituents thereof, respectively, have one or more hydrogen atoms optionally replaced by deuterium;

in a particular embodiment of the invention, R ²⁹ 、R ³³ 、R ⁴³ Independently selected from H, CH ₃ And CD (compact disc) ₃ 。

In a particular embodiment of the invention, n, m, x, y are independently selected from 0 to 2; provided that the sum of the integers m and n of the residuum linked to one sulfur atom is independently selected from 0 to 2; provided that the sum of the residues bound to one sulfur atom, x and y, is independently selected from 1 or 2.

In a particular embodiment of the invention, ring A, ring B, ring C, R ² 、R ²⁷ 、R ²⁸ 、R ²⁹ 、R ³¹ 、R ³² 、R ³³ 、R ⁴¹ 、R ⁴² 、R ⁴³ And/or at least one hydrogen in X is replaced with deuterium.

In a particular embodiment of the invention, at least one hydrogen in rings C and X is replaced by deuterium. More particularly, at least three hydrogens in rings C and X are replaced with deuterium. Most particularly, at least four hydrogens in rings C and X are replaced with deuterium.

In a particular embodiment of the invention, R ¹ Is H and R ² Is H;

selected from->

-NR ² B is selected from

Selected from->

In a more specific embodiment of the invention, R ¹ Is H and R ² Is H;

selected from->/>

-NR ² B is selected from

Selected from->

In the most specific embodiment of the invention, R ¹ Is H and R ² Is H;

selected from->

-NR ² B is selected from

Selected from->

Specific compounds of the present invention are the compounds of the following examples of the present invention, more particularly the compounds of the following examples 1, 2 and 6.

Specific compounds of the invention are selected from

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Or a solvate or pharmaceutically acceptable salt thereof.

Specific compounds of the invention are selected from

Or a solvate or pharmaceutically acceptable salt thereof.

More particularly the compounds of the invention are selected from

Or a solvate or pharmaceutically acceptable salt thereof.

Most particularly the compounds of the invention are selected from

Or a solvate or pharmaceutically acceptable salt thereof.

According to the expert's knowledge, the compounds according to the invention and the salts thereof, for example, when isolated in crystalline form, may contain different amounts of solvent. Thus, all solvates of the compounds of formula (I), in particular all hydrates, and all solvates of the salts of the compounds of formula (I), in particular all hydrates, are included within the scope of the present invention.

The present invention also relates to a method of preventing and/or treating a disease, disorder, therapeutic indication or medical condition described herein, in particular a disease or medical condition that inhibits DHODH benefit, more in particular a disease selected from the group consisting of rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, diseases caused by viral infections and pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthrosis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as described herein. Similarly, the invention also relates to methods as described above, which encompass other embodiments described herein, in particular medical uses and compounds for medical treatment as described herein.

The present invention also relates to a method of preventing and/or treating a disease, disorder, therapeutic indication or medical condition described herein, particularly a disease or medical condition that inhibits DHODH benefit, more particularly a disease or medical condition selected from graft versus host and host versus graft response, rheumatoid arthritis, multiple sclerosis, myosallow lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, ulcerative colitis, crohn's disease, primary sclerosing cholangitis and psoriasis, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) as described herein.

The invention also relates to pharmaceutical compositions, kit of parts and kit of parts comprising the compounds of the invention.

The invention also relates to the use of a compound according to the invention for the preparation of a pharmaceutical composition for the treatment and/or prophylaxis of a disease, disorder, condition and/or illness as described herein.

The invention also relates to methods and medical uses described herein, encompassing pharmaceutical compositions as described herein.

The pharmaceutical compositions as described herein comprise one or more compounds according to the invention and a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions as described herein comprise one or more compounds according to the invention and a pharmaceutically acceptable carrier or excipient, and further comprise one or more additional therapeutic agents selected from the group consisting of anti-viral agents, anti-inflammatory agents, immunosuppressants and/or immunomodulators, compounds of the castanosperms, non-castanospermatic agents, antihistamines, analgesics, and suitable mixtures thereof.

Furthermore, the present invention relates to an article of manufacture comprising a packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent has a therapeutic effect on a medical condition as described herein, wherein the packaging material comprises a label or package insert indicating that the pharmaceutical agent is useful for preventing or treating the medical condition, and wherein the pharmaceutical agent comprises one or more compounds of formula (I) according to the present invention. The packaging materials, labels, and package inserts are otherwise similar or analogous to standard packaging materials, labels, and package inserts for pharmaceuticals that are generally considered to have a related utility.

The pharmaceutical compositions according to the invention are prepared by methods known per se and well known to the person skilled in the art. As pharmaceutical compositions, the compounds of the invention (=active compounds) can be used as such or in particular in combination with suitable pharmaceutical auxiliaries and/or excipients, for example in the form of tablets, coated tablets, capsules, caplets, suppositories, patches (e.g. as TTS), emulsions, suspensions, gels or solutions, the active compound content advantageously being between 0.1% and 95%, wherein by appropriate choice of auxiliaries and/or excipients a pharmaceutical administration form (e.g. delayed release form or enteric form) which is entirely suitable for the active compound and/or the desired onset of action can be obtained.

Adjuvants, vehicles, excipients, diluents, carriers or adjuvants suitable for use in the desired pharmaceutical formulations, preparations or compositions are well known to those skilled in the art for their expertise. In addition to solvents, gel formers, ointment bases and other active compound excipients, such as antioxidants, dispersants, emulsifiers, preservative agents, solubilizers, colorants, complexing agents or permeation enhancers, may also be used.

Depending on the particular disease to be treated or prevented, additional therapeutically active agents, which are typically administered in order to treat or prevent the disease, may optionally be co-administered with the compounds according to the invention. As used herein, additional therapeutic agents that are typically administered for the treatment or prevention of a particular disease are known to be appropriate for the disease being treated.

In another aspect of the invention, the compounds according to the invention or salts or solvates of the compounds of formula (I) may be combined with standard therapeutic agents commonly used in the treatment of medical conditions as described herein.

The person skilled in the art knows the total daily dose and the administration form of the additional therapeutic agent co-administered based on his expert knowledge. The total daily dose may vary within wide limits. In practicing the present invention, depending on the details, features, or objects of its use as described above, a compound according to the present invention may be administered alone, sequentially, simultaneously, or chronologically staggered (e.g., as a combined unit dosage form, as a separate unit dosage form or adjacent discrete unit dosage forms, as a fixed or non-fixed combination, as a kit of parts, or as a mixture) in combination therapy with one or more standard therapeutic agents, particularly chemotherapeutic agents or target-specific anticancer agents known in the art, such as those described above.

Thus, another aspect of the invention is a composition or pharmaceutical composition comprising a first active ingredient which is a compound according to the invention or a pharmaceutically acceptable salt or solvate thereof; a second active ingredient, which is a standard therapeutic agent known in the art for medical conditions as described herein; and optionally a pharmacologically acceptable carrier, diluent and/or excipient, for sequential, separate, simultaneous or chronologically staggered use in any order for treatment, e.g., for treatment, prevention or amelioration of a medical disorder as described herein in a patient. In this case, the invention also relates to a combination comprising a first active ingredient which is at least one compound according to the invention; and a second active ingredient that is at least one standard therapeutic agent known in the art for use in medical conditions as described herein, the combination being for use in therapy alone, sequentially, simultaneously or chronologically staggered, for example for the treatment of those diseases described herein.

The term "combination" according to the invention may exist in fixed combination, non-fixed combination or kit of parts. A "fixed combination" is defined as a combination in which the first active ingredient and the second active ingredient are present together in a single unit dose or single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and the second active ingredient are present in a mixture for simultaneous administration, such as in the form of a formulation. An alternative example of a "fixed combination" is a pharmaceutical combination, wherein the first active ingredient and the second active ingredient are present in one unit rather than being mixed.

A "kit of parts" is defined as a combination in which the first active ingredient and the second active ingredient are present in more than one unit. An example of a "kit of parts" is a combination in which the first active ingredient and the second active ingredient are present separately. The components of the kit of parts may be administered separately, sequentially, simultaneously or staggered in time sequence.

The first active ingredient and the second active ingredient of a combination or kit of parts according to the invention may be provided as separate formulations (i.e. independent of each other) which are subsequently together for simultaneous, sequential, separate or chronologically staggered use in combination therapy; or packaged together and provided as separate components of a combination package for simultaneous, sequential, separate or chronologically staggered use in combination therapy. The types of pharmaceutical formulations of the first active ingredient and the second active ingredient of the combination or kit according to the invention may be similar, i.e. the two ingredients are formulated in separate tablets or capsules, or may be different, i.e. adapted to different administration forms, e.g. one active ingredient is formulated as a tablet or capsule, and the other active ingredient is formulated for e.g. intravenous administration. The amounts of the first active ingredient and the second active ingredient of the combination, composition or kit according to the invention may together comprise a therapeutically effective amount for treating, preventing or ameliorating a medical disorder as described herein.

Another aspect of the invention is a method of co-therapeutically treating a medical condition as described herein in a patient in need thereof, the method comprising separately, sequentially, simultaneously administering to the patient a therapeutically effective and tolerable amount of one or more compounds according to the invention and a therapeutically effective and tolerable amount of one or more therapeutic agents known in the art for a medical condition as described herein.

The description and claims of the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for the treatment of a disease or medical condition, as such in its general and specific forms, are directed to corresponding methods of treating the disease or medical condition, which methods comprise administering to a subject in need thereof a therapeutically effective and tolerable amount of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof; a composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in the treatment of the disease or medical condition; a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, or vice versa, for use in the treatment of said disease or medical condition.

For the preparation of pharmaceutical compositions, the compounds (=active compounds) according to the invention are in particular admixed with suitable pharmaceutical auxiliaries and further processed to give suitable pharmaceutical preparations. Suitable pharmaceutical preparations are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions. The pharmaceutical compositions according to the invention are prepared by methods known per se.

The dosage of the active compounds is carried out in the customary order of magnitude. Thus, topical application forms (e.g., ointments) containing active compounds at concentrations of, for example, 0.1% to 99%. In the case of systemic treatment (oral), conventional doses are typically 0.3 to 30 mg/kg/day and (intravenous) typically 0.3 to 30mg/kg/h. The choice of the optimum dosage regimen and the duration of administration, in particular the optimum dosage and mode of administration of the active compound necessary in each case, can be determined by the person skilled in the art on the basis of his expert knowledge.

The class of compounds of the invention may be used to develop drugs suitable for the treatment of autoimmune or viral diseases and also of inflammation of a small size, or more generally, for the treatment of diseases in which inhibition of DHODH is beneficial. The compounds of the invention are also useful in the treatment of rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, diseases caused by viral infections and Pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation, or joint diseases. More specifically, the disease is selected from graft versus host and host versus graft reactions, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, influenza, ulcerative colitis, crohn's disease, primary sclerosing cholangitis, and psoriasis.

The class of compounds of the invention may be used to treat viral diseases, in particular selected from the group consisting of coronavirus infection, covd-19, SARS, influenza (and avian influenza), HIV/aids, fowl pox (varicella), cytomegalovirus, dengue fever, german measles (rubella), hand-foot-and-mouth disease, hantavirus infection, all forms of hepatitis, rasagile fever, marburg virus infection, measles, meningitis, MERS-CoV, mumps, norovirus infection, herpes simplex virus infection, smallpox, rotavirus infection, ebola virus, spinulomyelitis virus infection, rhinovirus infection, parainfluenza virus infection, RSV infection, HCMV infection and banna virus infection. Most preferred are covd-19, influenza and rhinovirus infections, most preferred is covd-19. It is understood that mutant forms of the virus (e.g., SARS-CoV-2) are also contemplated.

Combination or alternation therapy

The compounds as described herein, or pharmaceutically acceptable salts thereof, may be administered above the current standard of care of the patient, or in combination or alternation with any other compound or therapy deemed beneficial to the patient by the healthcare provider. The combination and/or alternation therapy may be therapeutic, auxiliary or palliative.

For the treatment of antiviral infections, in particular Covid-19, combination or alternation therapy is particularly preferred:

high levels of the cytokine interleukin-6 (IL-6) have been observed to be a precursor to respiratory failure and death in patients with COVID-19. To treat this immune response surge, which is likely to constitute a cytokine storm, a patient may be administered a monoclonal antibody that targets IL-6, a drug inhibitor, or a protein degrading agent such as a bispecific compound that binds to IL-6 and mediates degradation of the protein. Examples of antibodies include tolizumab, sha Lilu mab, stetuximab, olozumab, and clazab mab. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination or alternation with tolizumab or sarcanduzumab. Other non-limiting examples of immunosuppressive drugs for the treatment of the hyper-responsive immune system include Janus kinase inhibitors (tofacitinib, baritinib, fingolitinib); calcineurin inhibitors (cyclosporine), tacrolimus, mTOR inhibitors (sirolimus, everolimus) and IMDH inhibitors (thiozopurine). Other antibodies and biological agents include abasic, adalimumab, anakinra, sirtuin, canacezept, golimumab, infliximab, epezium, natalizumab, rituximab, threumab, tolizumab, you-tec monoclonal, vedolizumab, basiliximab, and darizumab.

IL-1 blocks the production of IL-6 and other pro-inflammatory cytokines. Covd patients are sometimes also treated with IL-1 therapy to reduce the high inflammatory response, such as intravenous administration of anakinra. anti-IL-1 therapies can generally be, for example, bispecific compounds that target monoclonal antibodies, drug inhibitors, or protein degradation agents, such as proteins that bind to IL-1 and mediate degradation.

Covd patients often develop viral pneumonia, which can lead to bacterial pneumonia. Severe covd-19 patients are also affected by sepsis or "septic shock. Treatment for secondary bacterial pneumonia of covd or for sepsis includes administration of antibiotics, such as macrolide antibiotics, including azithromycin, clarithromycin, erythromycins, or roxithromycin. Other antibiotics include amoxicillin, doxycycline, cefazel, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanic acid, or levofloxacin. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is thus administered in combination or alternation with an antibiotic, such as azithromycin. Some of these antibiotics, such as azithromycin, have independent anti-inflammatory properties. The medicine can be used as anti-inflammatory agent for patients with COVID, and has therapeutic effect on secondary bacterial infection.

A unique challenge in treating patients infected with covd-19 is that if the patient requires mechanical ventilation that is likely to last for up to or over 5 days, 10 days, or even 14 days, then relatively long-term sedation is required. For sustained pain during this treatment, analgesic agents may be added sequentially; for sustained anxiety, sedatives may be added sequentially. Non-limiting examples of analgesic agents include acetaminophen, ketamine, and PRN abbe substances (hydrogen molpadiok, fentanil, and morphine). Non-limiting examples of sedatives include melatonin, atypical antipsychotics with sedation-leading effects (olanzapine, quinothionine), isopropyl or dextromethorphan, haloperidol, and phenobarbital. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate of a salt, hydrate or polymorph thereof is administered in combination or alternation with an analgesic such as acetaminophen, ketamine, hydrogen molitor, fentanyl or morphine. In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt, solvate of a salt, hydrate or polymorph thereof is administered in combination or alternation with a sedative agent such as melatonin, olanzapine, quinosulfane, isopropyl phenol, dexmedetomidine, haloperidol or phenobarbital.

In one embodiment, the compounds of the invention are used in effective amounts in combination with a protease inhibitor such as PF-07304814, PF-00835231, PF-07321332 (nmatrelvir), lopinavir (lopinavir) or ritonavir (ritonavir). In a more particular embodiment, the protease inhibitor is PF-07321332 (Nemactevir).

In one embodiment, the compounds of the invention are used in an effective amount in combination with an RNA replication modulator such as N4-hydroxylnoside or a prodrug thereof. In a particular embodiment, the RNA replication modulator is an N4-hydroxyls pro-drug as described in WO 2019/113462. In a more specific embodiment, the RNA replication modulator is monolavir (molnupiravir).

In one embodiment, the compounds of the invention are used in an effective amount in combination with halotetrol (halofuginol) or an enantiomer, tautomer, solvate, or pharmaceutically acceptable salt thereof.

In one embodiment, the compounds of the invention are used in an effective amount in combination with dipyridamole or a solvate or pharmaceutically acceptable salt thereof.

In one embodiment, the compounds of the invention are used in an effective amount in combination with gemcitabine or a solvate or pharmaceutically acceptable salt thereof.

In one embodiment, an effective amount of a compound of the invention is used in combination with AT-527 (RO 7496998) or a solvate or pharmaceutically acceptable salt thereof.

Other drugs that may be used to treat patients with covd include, but are not limited to, aspirin, colchicine, dimethyl fumarate, acartinib, fapirrevir, fingolimod, methylprednisolone, bevanadin, tolizumab, wu Fennuo, losartan, and monoclonals combinations of REGN3048 and REGN3051 or ribavirin. Any of these drugs or vaccines can be used in combination or alternation with the active compounds provided herein to treat viral infections susceptible to such drugs.

In one embodiment, the compounds of the present invention are used in combination with anti-coronavirus vaccine therapies including, but not limited to, mRNA-1273 (Modner corporation), AZD-1222 (AZD corporation and oxford university), BNT162b2 (Biotechnology corporation), coronaVac (Koxing corporation), NVX-CoV 2372 (Nowa gas corporation), SCB-2019 (Sanof corporation and GSK), zyCoV-D (cadira corporation) and CoVaxin (Bara biotechnology). In another embodiment, the compounds of the invention are used in an effective amount in combination with an passive antibody therapy or convalescent plasma therapy.

SARS-CoV-2 is constantly mutated, with an increase in toxicity and transmission rate. After prolonged treatment with antiviral agents, drug-resistant viral variants are likely to occur. Resistance is likely to result from mutation of the gene encoding the enzyme used for viral replication. In some cases, the efficacy of an anti-RNA viral infection drug may be prolonged, enhanced or restored by the combination or alternate administration of the compound with another, possibly even two or three other antiviral compounds that induce mutations that differ from the primary drug or act through different pathways. Variants of a known virus may refer to viruses that carry one or more nucleotide mutations, e.g., 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 in the viral genome as compared to the known virus. Mutations may refer to nucleotide deletions, insertions or substitutions. In some cases, the variant viral genome may differ from a known viral genome by up to 50%, 40%, 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1%.

Alternatively, the pharmacokinetics, biodistribution, half-life or other parameters of the drug may be altered by such combination therapy (which may include alternating therapies if consistent is contemplated).

Examples of other therapeutic agents that may be combined with the compound of formula (I) or a pharmaceutically acceptable salt, solvate of a salt, hydrate or polymorph thereof include, but are not limited to:

(1) A protease inhibitor;

(2) A polymerase inhibitor (e.g., gemcitabine);

(3) A allosteric polymerase inhibitor;

(4) Interferon alpha-2 a and/or ribavirin, which is likely to be pegylated or otherwise modified;

(5) A non-substrate-based inhibitor;

(6) A helicase inhibitor;

(7) Primer enzyme-helicase inhibitors;

(8) Antisense oligonucleotides (S-ODNs);

(9) A fitness;

(10) Ribozyme resistance ribozyme;

(11) iRNA, including micrornas and sirnas;

(12) Antibodies, partial antibodies or domain antibodies to the virus;

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

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

(15) Glutamyl-and aminoacyl-tRNA synthetase inhibitors (e.g., halofuranones);

(16) Balanced nucleoside transporter (ENT) inhibitors (e.g., binghattimo);

(17) Other DHODH inhibitors (e.g., buquina, teflon, leflunomide, PTC299, MEDS433, AG-636, ASLAN003, JNJ-74856665, RP7214, PP-001, and BAY 2402234).

It will be appreciated that depending on the source of chemical material used in the synthesis, there may be some variation in natural isotope abundance in the synthesized compound. Thus, formulations of vedoraforolamol (and other compounds of formula (I) particularly substituted with deuterium) will inherently contain a small amount of deuterated isotope analogue. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotope substitution of the compounds of the invention. See, e.g., comp. 119A:725.

The term "isotopically enriched factor" at a particular position typically occupied by hydrogen is the ratio of the abundance of deuterium at that position to the natural abundance of deuterium at that position. For example, isotopically enriched factor 3500 means that the amount of deuterium at a particular position is 3500 times the natural abundance of deuterium, or that 52.5% of the compound has deuterium at a particular position (i.e., 52.5% deuterium is incorporated at a given position). Deuterium abundance in the earth's ocean is about 6500 hydrogen atoms in one atom (about 154 parts per million (ppm)). Thus, deuterium comprises about 0.015% (0.030% by weight) of all naturally occurring hydrogen atoms in the ocean on earth; the abundance varies slightly from one natural water to another.

When a particular position in a compound of the invention (e.g., a compound represented by formula (I) or a pharmaceutically acceptable salt and/or solvate thereof) is designated by name or structure as containing hydrogen or deuterium, it is to be understood that the position may contain hydrogen in its natural abundance or may be enriched with deuterium, where the isotopic enrichment factor is, for example, at least 835 (12.5% deuterium incorporation), at least 1670 (25% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

When a particular position in a compound of the invention (e.g., a compound represented by formula (I) or a pharmaceutically acceptable salt and/or solvate thereof) is explicitly designated by a name or structure as "H" or "hydrogen," that position should be understood to be hydrogen having its natural abundance isotopic composition.

When a particular position in a compound of the invention (e.g., a compound represented by formula (I) or a pharmaceutically acceptable salt and/or solvate thereof) is explicitly designated by name or structure as "D" or "deuterium", it is understood that the deuterium abundance at that position is at least 3340 times the deuterium natural abundance, i.e., at least 50.1% deuterium incorporation, at least 3500 times the deuterium natural abundance (52.5% deuterium incorporation), at least 4500 times the deuterium natural abundance (67.5% deuterium incorporation), at least 5000 times (75% deuterium), at least 5500 times the deuterium natural abundance (82.5% deuterium incorporation), at least 6000 times the deuterium natural abundance (90% deuterium incorporation), at least 6333.3 times the deuterium natural abundance (95% deuterium incorporation), at least 6466.7 times the deuterium natural abundance (97% deuterium incorporation), at least 6600 times the deuterium natural abundance (99% deuterium incorporation), or at least 6633.3 times the deuterium natural abundance (99.5% deuterium incorporation).

Deuterium incorporation into the percentage ratio can be quantified by using a number of conventional methods such as mass spectrometry (peak area), or by signal with an internal standard or other non-deuterated species in the compound ¹ Quantification of the residual residues of the specific deuterated sites compared to the H signal ¹ H-NMR signal.

When the chemical name or structure does not indicate whether a particular position in the compound that is normally occupied by hydrogen is isotopically enriched, it is desirable that said particular position be occupied by hydrogen in its natural abundance. For example, the term "phenyl" or

Without any further explanation regarding isotopic enrichment, it is meant that all hydrogen atoms are present in natural abundance.

When ring a is a partially saturated ring, the double bond in ring a is located at the position:in the case where ring a is a 5 membered heteroaryl ring, then the double bond is within the ectopic pi system and may exist in meso form. One example is the lower thiophene meso form: />

Furthermore, the compounds of the present invention are partially tautomeric. For example, if a heteroaromatic group containing a nitrogen atom on the ring is substituted with a hydroxyl group on a carbon atom adjacent to the nitrogen atom, the following tautomerism may occur:

the term "1,4-orientation" (as described for ring B) means a specific relative position of two substituents on the same ring and means that there is at least one possibility for a substituent on a ring in which 4 atoms are located in the ring between the two substituents to which the ring system is attached:

When referring to any compound of the present disclosure, including compounds represented by formula (I) or pharmaceutically acceptable salts and/or solvates thereof, the term "compound" is intended to refer to a collection of molecules having the same chemical structure, but with the possibility of isotopic variation in the constituent hydrogen atoms of the molecules. The relative amount of isotopic variation in the compounds of the present invention will depend on a number of factors including the isotopic purity of the deuterating reagent used to make said compounds and the deuterium incorporation efficiency in the various synthetic steps used to prepare said compounds.

Both "D" and "D" are deuterium. "H" is hydrogen.

"substituted with deuterium" means that one or more hydrogen atoms are replaced with a corresponding number of deuterium atoms.

Any formula or structure given herein is also intended to mean deuterated compounds that additionally contain other isotopically labeled atoms. Examples of other isotopes that can be incorporated into compounds of the present disclosure also include isotopes of hydrogen (i.e., tritium or tritium ³ H) Isotopes of carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as but not limited to ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁸ F、 ³¹ P、 ³² P、 ³⁵ S、 ³⁶ Cl and Cl ¹²⁵ I. The present disclosure also includes compositions wherein a radioisotope such as ³ H、 ¹³ C and C ¹⁴ Various isotopically labeled compounds of C. Such isotopically-labeled compounds can be used in metabolic studies, kinetic studies, detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays or radiation treatment of patients.

Halogen is selected from fluorine, chlorine, bromine and iodine, more preferably fluorine or chlorine, most preferably fluorine.

In the context of the present invention, "C _1-4 Alkyl "means a preferably saturated hydrocarbon chain having 1 to 4 carbon atoms, which may be straight or branched. Examples thereof include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and tert-butyl. Preferably C _1-3 Alkyl groups such as methyl, ethyl, propyl and isopropyl, most preferably methyl. Unless otherwise indicated, the term "alkyl" by itself or as another substituent, e.g. halo-C _1-4 Also intended to include, when part of an alkyl group, those derivatives of an alkyl group which are defined in more detail below as "unsaturated alkyl groups". Unsaturated alkyl groups are alkyl groups having one or more double or triple bonds. Preferred unsaturated alkyl substituents are vinyl, 2-propenyl or prop-2-yn-1-yl.

In the context of the present invention, the term "C with one or more hydrogen atoms in the alkyl group optionally replaced by deuterium _1-4 Alkyl "embraces but is not limited to the following residues: -CD ₃ 、-CH ₂ D、-CHD ₂ 、CD ₃ CH ₂ (CH ₂ ) _n -、CD ₃ CH ₂ (CHD) _n -、CD ₃ CH ₂ (CD ₂ ) _n -、CH ₂ DCH ₂ (CH ₂ ) _n -、CH ₂ DCH ₂ (CHD) _n -、CH ₂ DCH ₂ (CD ₂ ) _n -、CHD ₂ CH ₂ (CH ₂ ) _n -、CHD ₂ CH ₂ (CHD) _n -、CHD ₂ CH ₂ (CD ₂ ) _n -、CD ₃ CHD(CH ₂ ) _n -、CD ₃ CHD(CHD) _n -、CD ₃ CHD(CD ₂ ) _n -、CH ₂ DCHD(CH ₂ ) _n -、CH ₂ DCHD(CHD) _n -、CH ₂ DCHD(CD ₂ ) _n -、CHD ₂ CHD(CH ₂ ) _n -、CHD ₂ CHD(CHD) _n -、CHD ₂ CHD(CD ₂ ) _n -、CH ₃ CHD(CH ₂ ) _n -、CH ₃ CHD(CHD) _n -、CH ₃ CHD(CD ₂ ) _n -、CD ₃ CD ₂ (CH ₂ ) _n -、CD ₃ CD ₂ (CHD) _n -、CD ₃ CD ₂ (CD ₂ ) _n -、CH ₂ DCD ₂ (CH ₂ ) _n -、CH ₂ DCD ₂ (CHD) _n -、CH ₂ DCD ₂ (CD ₂ ) _n -、CHD ₂ CD ₂ (CH ₂ ) _n -、CHD ₂ CD ₂ (CHD) _n -、CHD ₂ CD ₂ (CD ₂ ) _n -、CH ₃ CD ₂ (CH ₂ ) _n -、CH ₃ CD ₂ (CHD) _n -、CH ₃ CD ₂ (CD ₂ ) _n -, where n is an integer from 0 to 2, and CH ₃ CH ₂ (CHD) _m -、CH ₃ CH ₂ (CD ₂ ) _m -, where m is an integer from 0 to 2, and-CD (CD ₃ ) ₂ 、-CH(CD ₃ ) ₂ and-C (CD) ₃ ) ₃ . Preferred deuterium containing C _1-2 -alkyl is-CD ₃ and-CD ₃ CD ₂ Most preferably-CD ₃ 。

“C _0-6 Alkylene "means that the corresponding group is divalent and links the attached residue to the rest of the molecule. Furthermore, in the context of the present invention, "C ₀ Alkylene "means a bond, and C ₁ Alkylene means a methylene linker, C ₂ Alkylene means an ethylene linker or a methyl-substituted methylene linker, and so on. In the context of the present invention, C _0-6 Alkylene preferably represents a bond, methylene, ethylene or propylene group. Unless otherwise indicated, the term "alkylene" is also intended to include unsaturated divalent chains where appropriate (i.e., for "C _2-6 Alkylene "is possible). Unsaturated C ₄ Representative examples of alkylene groups are-CH ₂ -CH＝CH-CH ₂ -。

The term "fluoro-C _1-4 -alkyl "or" O-fluoro-C _1-4 Alkyl "means that one or more hydrogen atoms in the alkyl chain are replaced by one or more fluorine atoms, respectively. Preferably CHF ₂ 、CF ₃ 、CH ₂ CF ₃ And CF (compact F) ₂ CF ₃ . More preferred examples thereof are the formation of-CF ₃ A group.

Is equally applicable to' halogen-C _1-4 -alkyl "or" O-halo-C _1-4 Alkyl ", which means that one or more hydrogen atoms in the alkyl chain are replaced by one or more halogen atoms independently selected from fluorine, chlorine, bromine and iodine.

In the context of the present invention, the term "fluoro-C with one or more hydrogen atoms in the alkyl group optionally replaced by deuterium _1-4 -alkyl "means if fluorine-C _1-4 The alkyl group contains one or more hydrogen atoms, then the one or more hydrogen atoms may be replaced by fluorine, thereby yielding a C as described above for the term "optionally with deuterium replacement of one or more hydrogen atoms in the alkyl group" _1-4 Alkyl "is the same as described. It should be understood that fluorine-C _1-4 The alkyl groups may also be fully fluorinated. fluorine-C preferably containing deuterium _1-2 Alkyl radicals, e.g.CDF ₂ 、CD ₂ CF ₃ And CD (compact disc) ₂ CF ₂ D. Most preferably CDF ₂ 。

"3-10 membered cycloalkyl" group means a saturated or partially unsaturated monocyclic, bicyclic, spiro, or polycyclic ring system containing from 3 to 10 carbon atoms, wherein each atom forming the ring system (i.e., the backbone atom) is a carbon atom. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, bicyclo [2.2.2]Octyl and bicyclo [3.2.1]Octyl, spiro [3.3 ]]Heptyl and bicyclo [2.2.1]Heptyl, adamantyl and pentacyclic [4.2.0.0 ^2,5 .0 ^3,8 .0 ^4,7 ]Octyl. Thus, a 3-6 membered cycloalkyl group means a saturated or partially unsaturated monocyclic, bicyclic or spiro ring system comprising 3 to 6 carbon atoms, while a 5-8 membered cycloalkyl group means a saturated or partially unsaturated monocyclic, bicyclic or spiro ring system comprising 5 to 8 carbon atoms.

The term "3-6 membered cycloalkyl" embraces, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, bicyclo [2.1.0] pentyl and spiro [2.3] hexyl. More preferably cyclopropyl or cyclobutyl.

The term "C _3-4 Cycloalkyl "having one or more hydrogen atoms in the alkyl group optionally replaced by deuterium, although this is not limited to the following residues:

cycloalkyl or heterocyclic groups may be linked straight or spiro, for example, when the cyclohexane is substituted with a heterocycloalkyl group, oxetane, may be of the structure:

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"3-10 membered heterocycloalkyl" group containing 1 to 4 heteroatoms independently selected from N, O and S means a saturated or partially unsaturated 3-10 membered carbon monocyclic, bicyclic, spiro, or polycyclic ring wherein 1, 2, 3, or 4 carbon atoms are each substituted with 1, 2, 3, or 4 carbon atoms,3 or 4 heteroatoms, wherein the heteroatoms are independently selected from N, O or S. The sulfur heteroatom in the ring may also be oxidized to s=o or SO ₂ . Carbon atoms in the ring may also oxidize to c=o. Examples thereof include oxacyclopropyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, pethidyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, 4-quinuclidinyl, 1,4-dihydropyrazolyl and 6-azabicyclo [3.2.1]Octyl. The heterocycloalkyl group may be attached to the remainder of the molecule through a carbon, nitrogen (e.g., in morpholine or piperidine) or sulfur atom. An example of an S-linked heterocycloalkyl group is a cyclic sulphonated imide amide

The term "3-6 membered heterocycloalkyl" encompasses, but is not limited to, oxacyclopropyl, oxacyclobutyl, pyrrolidinyl, tetrahydrofuranyl, pethidyl, 2-oxaspiro [3.3] heptyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, and the like.

"6-or 10-membered aryl" is phenyl or naphthyl.

"5-to 10-membered heteroaryl containing 1 to 6 heteroatoms independently selected from N, O and S" means a 5-to 10-membered monocyclic or bicyclic heteroaromatic ring system (also referred to herein as heteroaryl) containing up to 6 heteroatoms independently selected from N, O and S. Examples of monocyclic heteroaromatics include pyrrolyl, imidazolyl, furanyl, thienyl, pyrazoloyl, sideroyl, pyrazoloyl, oxazolyl, isoxazolyl, triozolyl, oxadiazolyl, and thiadiazolyl. It also means a bicyclic ring system in which the heteroatom may be present in one or both rings, including bridgehead atoms. Examples thereof include quinolyl, isoquinolyl, quinolyl, benzoimidazolyl, benzoisoxazolyl, benzofuranyl, benzooxazolyl, indolyl 1,5-naphthalenecinyl, 1,7-naphthalenecinyl, and pyrazolo [1,5-a ] jicinyl. The nitrogen or sulfur atoms of the heteroaryl system may also optionally be oxidized to the corresponding N-oxide, S-oxide or S, S-dioxyde.

"5-membered heteroaryl" means a monocyclic aromatic ring system containing up to 3 heteroatoms independently selected from N, O and S. Examples of monocyclic heteroaromatic rings include pyrrolyl, imidazolyl, furanyl, thienyl and oxazolyl. The sulfur heteroatom in the ring may also be oxidized to s=o or SO ₂ 。

By 5-membered heterocyclopentyl group is meant a partially unsaturated 5-membered carbon monocyclic ring in which 1 or 2 carbon atoms are replaced by 1 or 2 heteroatoms, respectively, wherein the heteroatoms are independently selected from N, O and S. Examples include 2,3-dihydrofuryl, 2,5-dihydrofuryl, 2,5-dihydrothienyl or 2,5-dihydro-1H-pyrrole. The sulfur heteroatom in the ring may also be oxidized to s=o or SO ₂ 。

Depending on its structure, the compounds of the invention may exist in tautomeric or stereoisomeric forms (enantiomers, diastereomers). Thus, the present invention also encompasses tautomers, enantiomers or diastereomers and the corresponding mixtures thereof. The stereoisomerically homogeneous component may be separated from such enantiomer and/or diastereomeric mixtures in a known manner.

The term "diastereoisomers" means stereoisomers that are not mirror images of each other and that cannot overlap each other. 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 standard methods in the art) of at least 80% (i.e., at least 90% for one enantiomer and at most 10% for the other enantiomer), preferably at least 90%, more preferably at least 98%. The compounds of the present invention may be in the form of pro-drug compounds. "prodrugs" means derivatives which are converted to the compounds according to the present invention under in vivo physiological conditions by reaction with enzymes, gastric acid, etc., for example by oxidation, reduction, hydrolysis, etc., each of which is carried out enzymatically. Further examples of prodrugs are compounds wherein the carboxylic acid in the compounds of the present invention is converted, for example, to an alkyl, aryl alkylene, amino, choline, acyloxy alkyl, 1- ((alkoxycarbonyl) oxy) -2-alkyl or hypolinolenyl ester. Exemplary structures of prodrugs of carboxylic acids are

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable, non-toxic bases (including inorganic and organic bases). Thus, compounds of the present disclosure containing acidic groups may be present on these groups and may be used in accordance with the present disclosure as, for example, alkali metal salts, alkaline earth metal salts, or ammonium salts. More specific examples of such salts include sodium, potassium, calcium, magnesium salts, or salts containing ammonia or organic amines such as ethylamine, ethanolamine, triethanolamine or an amino acid. The corresponding salts can be obtained by customary methods known to the person skilled in the art, for example by contacting these compounds with organic or inorganic bases in solvents or dispersants, or by cation exchange with other salts. The present disclosure also includes all salts of the compounds of the present disclosure that are not directly useful in medicine due to low physiological compatibility, but are useful, for example, as intermediates for chemical reactions or for preparing pharmaceutically acceptable salts.

Furthermore, the compounds of the present disclosure may be present in the form of a solvate, such as a solvate comprising water or a pharmaceutically acceptable solvate, such as an alcohol solvate, in particular an ethanol solvate. Stoichiometric or non-stoichiometric amounts of solvent are bound by non-covalent intermolecular forces. When the solvent is water, the "solvolyte" is "hydrate". It will be appreciated that the "pharmaceutically acceptable salt" may also optionally contain a "solvate".

As used herein, the term "polymorph" refers to a crystalline form of a compound or salt, hydrate or solvate thereof in a particular crystal stacking arrangement. All polymorphs have the same elemental composition. As used herein, the term "crystalline" refers to a solid state form consisting of an ordered arrangement of structural units. Different crystalline forms of the same compound or salt, hydrate or solvate thereof result from different stacks of solid state molecules, which results in different crystal symmetry and/or unit cell parameters. Different crystalline forms typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardness, crystal shapes, optical and electrical properties, stability, and solubility.

The term "effective amount" is intended to include an amount of the compound that, when administered, is sufficient to prevent or to some extent alleviate the development of one or more symptoms of the disorder, disease or condition being treated. The term "effective amount" also refers to the amount of a compound that is being sought by a researcher, veterinarian, medical doctor or clinician sufficient to elicit the biological or medical response of a cell, tissue, system, animal or person.

As used herein, the term "subject" refers to any member of the animal kingdom, including humans. In some embodiments, a "subject" is a human being at any stage of development. In some embodiments, a "subject" is a human patient. In some embodiments, a "subject" is a non-human animal. In some embodiments, the non-human animal is a mammal (e.g., a rodent, mouse, rat, rabbit, monkey, dog, cat, sheep, cow, primate, or pig). In some embodiments, the subject includes, but is not limited to, a mammal, bird, reptile, amphibian, fish, or worm. In some embodiments, the subject may be a transgenic animal, a genetically engineered animal, or a clone.

Unexpectedly, it was found that deuterated compounds as detailed herein exhibit higher microparticle stability and improved pharmacokinetic properties in rats and mice. The following examples section shows more details.

Detailed Description

Experimental part

The compounds of the invention may be prepared as outlined in WO2003/006425 and WO2004/056797 (and references cited therein), either by using appropriate deuterated building blocks or by hydrogen-deuterium exchange (e.g. Synthesis 2019;51:1319 or angelw. Chem. Int. Ed.2018;57: 3022).

Abbreviations (abbreviations)

DBU 1,8-diazabicyclo [5.4.0] undec-7-ene

DMSO dimethyl sulfoxide

dppf 1,1' -bis (diphenylphosphino) ferrocene

EA ethyl acetate

FCC silica gel quick chromatographic method

PE Petroleum ether

rt room temperature (20+ -4 ℃ C.)

Experimental part

Preparation example P1:

step 1:5-bromo-1-fluoro-3- (methoxy-d 3) -2-nitrobenzene (P1 a)

CD can be used in KOH similarly to that described in WO2018/059314 ₃ OD treatment of 5-bromo-1,3-difluoro-2-nitrobenzene gives the target compound P1a.

Step 2:4-bromo-2-fluoro-6- (methoxy-d 3) aniline (P1)

Similar to that described in WO2018/059314, the desired compound P1 can be obtained by treating the complex P1a with hydrazine hydrate and raney nickel as catalysts.

Preparation example P2:1- (3 lambda) ⁶ -propyloxy-d 9) -3-bromobenzene (P2)

By reacting 1-iodo-3λ ⁶ Propane-1,1,2,2,3,3,3,3,3-d 9 was reacted with 3-bromophenol and potassium carbonate in DMF to prepare compound P2.

Preparation example P3:2,6-difluoro-4- (morpholino-d 8) aniline (P3)

The target compound P3 can be prepared similarly to WO2008/018426 by reacting tert-butyl (4-bromo-2,6-difluorophenyl) carbamate with morpholine-2,2,3,3,5,5,6,6-d 8 in toluene at 60 ℃ for 14 hours using palladium diacetate, 2-dicyclohexylphosphino-2 ',6' -dimethoxybiphenyl and potassium tert-butoxide, deprotecting the Boc group with 4N HCl/dioxane and treating the aqueous solution under basic conditions.

Preparation example P4:

step 1:bicyclo [2.2.2]Octane-1,4-dicarboxylic acid 1- (1,3-dioxoisoindolin-2-yl) ester 4-methyl ester (P4 a)

Dicyclohexylcarbodiimide and 4- (dimethylamino) pyridine were used as catalysts in the presence of CH ₂ Cl ₂ Intermediate reacting 4- (methoxycarbonyl) bicyclo [2.2.2]Octane-1-carboxylic acid was coupled with phthalimide.

Step 2:4- (3-methoxyphenyl) bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (P4 b)

Similar to j.am.chem.soc.2016;138:11132, using 1,2-bis (diphenylphosphino) benzene and iron (III) acetylacetonate (Fe (acac) ₃ ) As a catalyst, the compound P4a was coupled with bis (3-methoxyphenyl) zinc to give the objective compound P4b.

Step 3:4- (3-hydroxyphenyl) bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (P4 c)

At-78 ℃ to room temperature under CH ₂ Cl ₂ BBr for middle-aged use ₃ Treating the compound P4b to obtain the target compound P4c.

Step 4:4- (3- (methoxy-d 3) phenyl) bicyclo [2.2.2]Octane-1-carboxylic acid methyl ester (P4 d)

Analogously to what is described in step 2 of example 2, CD is used ₃ And I, alkylating the compound P4c to obtain a target compound P4d.

Step 5:4- (3- (methoxy-d 3) phenyl) bicyclo [2.2.2]Octane-1-carboxylic acid (P4 e)

The compound P4d is saponified to obtain the target compound P4e.

Step 6:(4- (3- (methoxy-d 3) phenyl) bicyclo [ 2.2.2)]Octyl-1-yl) carbamic acid tert-butyl ester (P4 f)

Similar to that outlined in WO2016/045587, diphenylphosphoryl azide, boc, was used ₂ O and NEt ₃ Compound P4e was treated in t-butanol at reflux for 16 hours to give the target compound P4f.

Step 7:4- (3- (methoxy-d 3) phenyl) bicyclo [2.2.2]Oct-1-amine (P4)

The compound P4e was treated with 4N HCl/dioxane and treated with an aqueous solution under alkaline conditions to give P4.

Example 1:

step 1:2-fluoro-4- (4,4,5,5-tetramethyl1,3,2-Dioxyboroamyl-2-yl) aniline (1 a)

To a solution of 4-bromo-2-fluoroaniline (4.00 g,21.1 mmol) in 1,4-dioxane (30 mL) was added bis (pinacolato) diboron (5.38 g,21.2 mmol), KOAc (6.23 g,63.5 mmol) and Pd (dppf) Cl ₂ (776 mg,1.1 mmol). The mixture was then heated at 90 ℃ for 1 hour, cooled to room temperature, filtered, concentrated and purified by FCC (PE: ea= 8:1) to give compound 1a as a white solid.

Step 2:3-fluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl]-4-amine (1 b)

To compound 1a (800 mg,3.37 mmol) in 1,4-dioxane (10 mL) and H ₂ To a solution of 1-bromo-3- (methoxy-d 3) benzene (428 mg,3.36 mmol), na was added in O (1 mL) ₂ CO ₃ (1.07 g,10.1 mmol) and Pd (dppf) Cl ₂ (124 mg,0.17 mmol) and then the mixture was heated at 90 ℃ for 2 hours, cooled to room temperature, filtered, concentrated and purified by FCC (PE: ea=10:1) to give compound 1b as an oil.

Step 3:2- ((3-fluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) aminomethyl) cyclopent-1-ene-1-carboxylic acid (1)

A solution of compound 1b (120 mg, 545. Mu. Mol) and 1-cyclopentene-1,2-dicarboxylic anhydride (74 mg, 540. Mu. Mol) in DCM (2.5 mL) was heated at 40℃for 4 hours. The mixture was filtered and the filter cake was washed with MeCN (2 x 2 mL). The solid was dried in vacuo to give compound 1 as a pale yellow solid. ¹ H-NMR(400MHz,DMSO-d6)δ13.04(br s,1H),10.58(s,1H),8.07(t,J＝8.4Hz,1H),7.63(d,J＝12.4Hz,1H),7.53(d,J＝8.4Hz,1H),7.37(t,J＝8.0Hz,1H),7.27-7.23(m,2H),6.94(dd,J＝8.0,2.0Hz,1H),2.80(br s,2H),2.69(br s,2H),1.93-1.85(m,2H)。LCMS(ESI):m/z359.0(M+H) ⁺ 。

Examples 1/1 to 1/13:

the following examples were prepared analogously to example 1 above using the appropriate building blocks shown below.

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Example 2:

step 1:3-bromobenzene-2,4,6-d 3-ol (2 a)

1-bromo-3- (methoxy-d 3) benzene (800 mg,4.21 mmol) was added to 20mL DCl (35% D) ₂ O solution) was heated in an autoclave at 105℃for 2 days, cooled and quenched with Et ₂ O dilution. Separating the organic layer via Na ₂ SO ₄ Drying, concentrating and purifying by FCC (PE: ea=100:1 to 1:100) to give compound 2a as an oil.

Step 2:1-bromo-3- (methoxy-d 3) benzene-2,4,6-d 3 (2 b)

To a solution of 2a (300 mg,1.70 mmol) in MeCN (10 mL) was added methyl iodide-d3 (0.13 mL,2.1 mmol) and K ₂ CO ₃ (470 mg,3.41 mmol). The mixture was heated at 65 ℃ for 5 hours, cooled to room temperature, filtered, concentrated and purified by FCC (PE: ea=20:1) to give compound 2b as an oil.

Step 3:3-fluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl]-2',4',6' -d 3-4-amine (2 c)

To compound 1a (237 mg,1.00 mmol) in 1,4-dioxane (5 mL) and H ₂ To a solution of O (0.5 mL) was added compound 2b (192 mg, 994. Mu. Mol), na ₂ CO ₃ (0.32 g,3.0 mmol) and Pd (dppf) Cl ₂ (36 mg, 49. Mu. Mol) and then the mixture was heated at 90℃for 2 hours, cooled to room temperature, filtered and purified by FCC (PE: EA=10:1) to give compound 2c as an oil.

Step 4:2- ((3-fluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl-2 ',4',6' -d 3) aminomethyl) cyclopent-1-ene-1-carboxylic acid (2)

A solution of compound 2c (100 mg,0.45 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (62 mg,0.45 mmol) in DCM (2.5 mL) was heated at 40℃for 4 h. The mixture was filtered and the filter cake was washed with MeCN (2 x 2 mL). The solid was dried in vacuo to give compound 1b as a yellow solid. ¹ H-NMR(500MHz,DMSO-d6)δ13.04(br s,1H),10.57(s,1H),8.07(t,J＝7.8Hz,1H),7.63(d,J＝12.5Hz,1H),7.53(d,J＝8.0Hz,1H),7.37(s,1H),2.80(br s,2H),2.69(br s,2H),1.93-1.85(m,2H)。LCMS(ESI):m/z 362.0(M+H) ⁺ 。

Examples 2/1 to 2/2:

the following examples were prepared analogously to those described in examples 1 and 2 above using the appropriate building blocks shown below.

Example 3:

step 1:2- (3-Bromobenzyloxy-2,4,6-d 3) -2,2-difluoroacetic acid ethyl ester (3 a)

To a suspension of compound 2a (2.0 g,11.4 mmol) and DBU (4.3 g,28.2 mmol) in DMF (38 mL) was slowly added ethyl 2-bromo-2,2-difluoroacetate (5.8 g,28.6 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen for 16 hours, poured into water (50 mL) and extracted with EA (3×100 mL). The combined organic layers were purified by Na ₂ SO ₄ Drying, concentration and purification by FCC (PE: ea=10:1) gave compound 3a as a colorless oil.

Step 2:2- (3-Bromobenzyloxy-2,4,6-d 3) -2,2-difluoroacetic acid (3 b)

To a solution of compound 3a (2.8 g,9.4 mmol) in MeOH (20 mL) and THF (5 mL) was added 3M aqueous NaOH (5 mL). The mixture was stirred at room temperature for 30 min, acidified to pH 1, concentrated and purified by reverse phase chromatography (C18) (with 0.1% NH ₄ HCO ₃ H of (2) ₂ O/mecn=9:1 to 0:1 as gradient) to give compound 3b as an oil. LCMS (ESI): M/z 268.1 (M-H) ^- 。

Step 3:1-bromo-3- (trifluoromethoxy) benzene-2,4,6-d 3 (3 c)

To compound 3b (2.4 g,8.9 mmol) in CDCl ₃ XeF was added to the solution in (25 mL) ₂ (1.5 g,8.8 mmol). The mixture was stirred at room temperature for 10 minutes, concentrated and purified by FCC (PE: ea=40:1) to give compound 3c as a colorless oil.

Step 4:(3- (trifluoromethoxy) phenyl-2,4,6-d 3) boronic acid (3 d)

To a solution of compound 3c (1.3 g,5.3 mmol) in anhydrous THF (25 mL) was added n-BuLi (2.5M, 2.1mL,5.3 mmol) at-78deg.C. The mixture was stirred for 30 minutes, then a solution of triisopropyl borate (1.5 g,8.0 mmol) in anhydrous THF (5 mL) was added dropwise while stirring and cooling to maintain the temperature at about-78 ℃. After the addition, the mixture was stirred at this temperature for 30 minutes and then warmed to room temperature over a period of 1 hour. 2N HCl (3.1 mL) was added with stirring, the resulting mixture was concentrated, and the mixture was purified by reverse phase chromatography (C18) (H with 0.1% TFA) ₂ O/mecn=9:1 to 0:1 as gradient) to give compound 3d as a white solid. LCMS (ESI) M/z 208.2 (M-H) ^- 。

Step 5: 2,3,5,6-tetrafluoro-3 '- (trifluoromethoxy) - [1,1' -biphenyl]-2',4',6' -d 3-4-amine (3 e)

To compound 3d (150 mg,0.72 mmol) in 1,2-dimethoxyethane (3 mL) and H ₂ To a solution of 4-bromo-2,3,5,6-tetrafluoroaniline (174 mg,0.71 mmol), cs were added in O (0.6 mL) ₂ CO ₃ (702 mg,2.15 mmol) and Pd (PPh) ₃ ) ₄ (46 mg, 40. Mu. Mol). The mixture was heated at 90℃for 3 hours, cooled and diluted with EA (20 mL). Separating the organic layer via Na ₂ SO ₄ Dried, concentrated and purified by FCC (PE: ea= 8:1) to give compound 3e as a colorless oil. LCMS (ESI) M/z 329.2 (M+H) ⁺ 。

Step 6:2- ((2,3,5,6-tetrafluoro-3' - (tris)Fluoromethoxy) - [1,1' -biphenyl]-4-yl-2 ',4',6' -d 3) aminomethyl) cyclopent-1-ene-1-carboxylic acid (3)

A solution of compound 3e (100 mg,0.30 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (50 mg,0.36 mmol) in acetic acid (3 mL) was heated at 110℃for 4 hours, concentrated and purified by reverse phase chromatography (C18) (containing 0.1% NH) ₄ HCO ₃ H of (2) ₂ O/mecn=9:1 to 0:1 as gradient) to give compound 3 as a white solid. ¹ H-NMR(500MHz,CD ₃ OD)δ7.63(s,1H),2.94-2.89(m,2H),2.87-2.83(m,2H),2.03-1.97。LCMS(ESI):m/z 467.1(M+H) ⁺ ,489.2(M+Na) ⁺ 。

Example 4:

step 1:3- (Chlorocarbonyl) thiophene-2-carboxylic acid methyl ester (4 a)

To a solution of 2- (methoxycarbonyl) thiophene-3-carboxylic acid (200 mg,1.07 mmol) in anhydrous DCM (8 mL) was added SOCl ₂ (152 mg,1.28 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated to give compound 4a as a yellow solid, which was used in the next step without further purification.

Step 2:3- ((2,3,5,6-tetrafluoro-3 '- (trifluoromethoxy) - [1,1' -biphenyl)]-4-yl-2 ',4',6' -d 3) aminomethyl) thiophene-2-carboxylic acid (4)

To a solution of compound 3e (100 mg,0.30 mmol) in anhydrous THF (2 mL) was added NaH (60%, 30mg,0.75 mmol) at 0deg.C. The mixture was stirred at this temperature for 1 hour, then a solution of compound 4a (150 mg,0.73 mmol) in anhydrous THF (1 mL) was added dropwise at 0 ℃.After the addition, the mixture was stirred at this temperature for 30 minutes, then warmed to room temperature and stirred for 1 hour. Water (1 mL) was then added and stirring continued for 1 hour. The resulting mixture was then concentrated and purified by reverse phase chromatography (C18) (H with 0.1% TFA) ₂ O/mecn=9:1 to 0:1 as gradient) to give compound 4 as a white solid. ¹ H-NMR(400MHz,DMSO-d6)δ12.11(br s,1H),11.35(s,1H),7.94(d,J＝5.2Hz,1H),7.71(s,1H),7.44(d,J＝5.2Hz,1H)。LCMS(ESI):m/z 483.1(M+H) ⁺ ,505.1(M+Na) ⁺ 。

Example 4/1:

the following examples were prepared analogously to example 4 above using the appropriate building blocks shown below.

Example 5:

step 1:1-bromo-3- (difluoromethoxy-d) benzene (5 a)

To a solution of 3-bromophenol (560 mg,3.25 mmol) in anhydrous THF (10 mL) at 0deg.C was added NaH (1.3 g,60% w/w,33 mmol) and the mixture stirred at 0deg.C for 30 min, then D was added dropwise at 0deg.C ₂ O (6.5 mL) for 10 minutes. After addition of diethyl (bromodifluoromethyl) phosphonate (1.7 g,6.5 mmol), the mixture was stirred at room temperature for 30 min. The mixture was extracted with EA (3X 20 mL). The combined organic layers were washed with brine (100 mL), and dried over Na ₂ SO ₄ Drying, concentration and purification by FCC (PE: ea=40:1) gave compound 5a as a colorless oil.

Step 2:3'- (difluoromethoxy-d) -3-fluoro- [1,1' -linkageBenzene]-4-amine (5 b)

To compound 5a (250 mg,1.12 mmol) in 1,4-dioxane (6 mL) and H ₂ To a solution of O (0.6 mL) was added compound 1a (265 mg,1.12 mmol), na ₂ CO ₃ (356 mg,3.36 mmol) and Pd (dppf) Cl ₂ (41 mg,0.06 mmol). The mixture was heated at 90 ℃ for 2 hours and cooled. The organic layer was separated, concentrated and purified by FCC (PE: ea=10:1) to give compound 5b as a colorless oil.

Step 3:2- ((3 '- (difluoromethoxy-d) -3-fluoro- [1,1' -biphenyl)]-4-yl) aminomethyl) cyclopent-1-ene-1-carboxylic acid (5)

To a solution of compound 5b (70 mg,0.28 mmol) in DCM (2.5 mL) was added 1-cyclopentene-1,2-dicarboxylic anhydride (39 mg,0.28 mmol) and the mixture was then heated at 40℃for 4 h. The mixture was cooled to room temperature, filtered and the filter cake was washed with MeCN (2 x 2 mL). The solid was dried in vacuo to give compound 5 as a pale yellow solid. ¹ H-NMR(500MHz,DMSO-d6)δ13.04(br s,1H),10.70(s,1H),8.12(t,J＝8.0Hz,1H),7.68(d,J＝12.5Hz,1H),7.60-7.50(m,4H),7.18(d,J＝7.0,1H),2.80(br s,2H),2.70(br s,2H),1.92-1.86(q,J＝2.5Hz,2H)。LCMS(ESI):m/z393.3(M+H) ⁺ 。

Example 6:

step 1:4-bromo-2-fluorobenzene-6-d-amine (6 a)

4-bromo-2-fluoroaniline (2.0 g,10.6 mmol) was reacted in 15mL of DCl (35% D) ₂ O solution) was heated in an autoclave at 105 ℃ for 7 days. The solution was cooled to room temperature and conditioned with 6N NaOH To ph=8 and extracted with EA (3×20 mL). The combined organic layers were washed with brine (100 mL), and dried over Na ₂ SO ₄ Dried, concentrated and purified by FCC (PE: ea=10:1) to give compound 6a as an oil.

Step 2:2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzene-6-d-amine (6 b)

To a solution of compound 6a (1.0 g,5.3 mmol) in 1,4-dioxane (12 mL) was added bis (pinacolato) diboron (1.3 g,5.3 mmol), KOAc (1.56 g,15.9 mmol) and Pd (dppf) Cl ₂ (190 mg,0.26 mmol). The mixture was then heated at 90 ℃ for 1 hour, cooled to room temperature, filtered, concentrated and purified by FCC (PE: ea=10:1) to give compound 6b as a white solid.

Step 3: 3-fluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl]-5-d-4-amine (6 c)

To compound 6b (380 mg,1.60 mmol) in 1,4-dioxane (5 mL) and H ₂ To a solution of 1-bromo-3- (methoxy-d 3) benzene (302 mg,1.60 mmol), na was added in O (0.5 mL) ₂ CO ₃ (0.51 g,4.8 mmol) and Pd (dppf) Cl ₂ (58 mg,0.08 mmol). The mixture was stirred at 90 ℃ for 2 hours and then cooled to room temperature. The organic layer was separated, concentrated and purified by FCC (PE: ea=10:1) to give compound 6c as an oil.

Step 4:2- ((3-fluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl) ]-4-yl-5-d) aminomethyl) cyclopenta-1- Alkene-1-carboxylic acid (6)

A solution of compound 6c (80 mg,0.36 mmol) and 1-cyclopentene-1,2-dicarboxylic anhydride (50 mg,0.36 mmol) in DCM (2.5 mL) was stirred at 40℃for 4 h, cooled to room temperature and filtered. The filter cake was washed with MeCN (2 x 2 mL). The solid was dried in vacuo to give compound 6 as a yellow solid. ¹ H-NMR(500MHz,DMSO-d6)δ13.04(br s,1H),10.58(s,1H),7.63(dd,J＝12.5,2.0Hz,1H),7.53(d,J＝1.5Hz,1H),7.37(t,J＝8.0Hz,1H),7.26(d,J＝8.5Hz,1H),7.23-7.22(m,1H),6.94(dd,J＝8.3,2.3Hz,1H),2.80(t,J＝7.3Hz,2H),2.70(t,J＝7.3Hz,2H),1.89(p,J＝7.6Hz,2H)。LCMS(ESI):m/z 360.3(M+H) ⁺ 。

Example 7:2- ((3-fluoro-3 ' -hydroxy- [1,1' -biphenyl ] -4-yl-2 ',4',5,6' -d 4) aminomethyl) cyclopent-1-ene-1-carboxylic acid (7)

By applying the routes outlined above, the target compound is obtained by using the appropriate building block. ¹ H-NMR(500MHz,DMSO-d6)δ13.03(br s,1H),10.54(s,1H),9.54(s,1H),7.51(dd,J＝12.3,1.8Hz,1H),7.44(d,J＝1.5Hz,1H),7.25(s,1H),2.79(t,J＝7.0Hz,2H),2.68(t,J＝7.0Hz,2H),1.89(p,J＝7.0Hz,2H)。LCMS(ESI):m/z 346.3(M+H) ⁺ 。

Example 8:2- ((3-fluoro-3 ' -hydroxy- [1,1' -biphenyl ] -4-yl-2 ',4',6' -d 3) aminomethyl) cyclopent-1-ene-1-carboxylic acid (8)

By applying the routes outlined above, the target compound is obtained by using the appropriate building block. ¹ H-NMR(500MHz,DMSO-d6)δ10.68(br s,1H),9.55(s,1H),8.06(dd,J＝8.0,9.0Hz,1H),7.50(d,J＝12.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.25(s,1H),2.79-2.78(m,2H),2.69-2.68(m,2H),1.92-1.86(m,2H)。LCMS(ESI):m/z 345.3(M+H) ⁺ 。

Example 9:

step 1:2,6-difluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (9 a)

To a solution of 4-bromo-2,6-difluoroaniline (10 g,48 mmol) in 1,4-dioxane (100 mL) was added bis (pinacolato) diboron (12.8 g,50.4 mmol), CH ₃ COOK (14.1 g,144 mmol) and Pd (dppf) Cl ₂ (1.0 g,2.40 mmol). The mixture was heated to 90℃under N ₂ Stirred for 2 hours, cooled to room temperature, concentrated and purified by FCC (PE: ea=10:1) to give compound 9a as a yellow solid.

Step 2:3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl]-4-amine (9 b)

To compound 9a (4.5 g,13.3 mmol) in 1,4-dioxane (50 mL) and H ₂ To a solution of 1-bromo-3- (methoxy-d 3) benzene (3.34 g,13.3 mmol), na was added in O (5 mL) ₂ CO ₃ (5.61 g,39.4 mmol) and Pd (dppf) Cl ₂ (400 mg,0.67 mmol). The mixture was heated to 90℃under N ₂ Stirred for 2 hours, cooled to room temperature, concentrated and purified by FCC (PE: ea=10:1) to give compound 9b as a yellow solid. LCMS (ESI) M/z 239.1 (M+H) ⁺ 。

Step 3:2- ((3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) aminomethyl) cyclopent-1-ene-1-carboxylic acid (9)

To a solution of compound 9b (3.40 g,14.3 mmol) in DCM (20 mL) was added 1-cyclopentene-1,2-dimethylanhydride (1.90 g,14.3 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and the filter cake was washed with MeCN. Drying in vacuumThe solid was dried to give compound 9 as a white solid. ¹ H-NMR(500MHz,DMSO-d6)δ12.95(br s,1H),10.13(s,1H),7.55(d,J＝8.0Hz,2H),7.39(t,J＝7.8Hz,1H),7.32-7.28(m,2H),6.99(dd,J＝1.8,8.3Hz,1H),2.81-2.79(m,2H),2.69-2.66(m,2H),1.97-1.89(m,2H)。LCMS(ESI):m/z 377.3(M+H) ⁺ 。

Example 10:4- ((3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl ] -4-yl) aminomethyl) -2,5-dihydrothiophene-3-carboxylic acid (10)

By reacting 4,6-dihydro-1H, 3H-thieno [3,4-c, similarly as described above]Furan-1,3-dione reactions (synthesis and coupling are described in bioorg. Med. Chem. Lett.2005; 15:4854) gave target molecule 10. ¹ H-NMR(400MHz,DMSO-d6)δ13.01(br s,1H),10.20(s,1H),7.54(d,J＝9.2Hz,2H),7.39(t,J＝7.8Hz,1H),7.32-2.28(m,2H),6.99(dd,J＝2.4,8.0Hz,1H),4.15-4.11(m,2H),4.03-4.00(m,2H)。LCMS(ESI):m/z 395.2(M+H) ⁺ 。

Example 11:

step 1:4,6-dihydro-1H, 3H-furo [3,4-c]Furan-1,3-dione

To 4,6-dihydro-1H, 3H-thieno [3,4-c]To a solution of furan-1,3-dione (400 mg,2.23 mmol) (see biorg. Med. Chem. Lett.2005; 15:4854) in toluene (5 mL) was added AcCl (385 mg,4.92 mmol), and the mixture was stirred at 110 ℃ for 4 hours, cooled to room temperature and concentrated in vacuo to give compound 11a as a yellow solid which was used in the next step without purification. LCMS (ESI) M/z=140.1 (m+h) ⁺ 。

Step 2:4- ((3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) aminomethyl) -2,5-dihydrofuran-3-carboxylic acid (11)

Similarly as described above, the compound 11a is reacted to obtain the target molecule 11 as a white solid. ¹ H-NMR(500MHz,DMSO-d6)δ10.89(br s,1H),7.58(d,J＝9.5Hz,2H),7.39(t,J＝7.8Hz,1H),7.33-2.28(m,2H),6.99(dd,J＝2.3,8.3Hz,1H),4.97(t,J＝5.3Hz,2H),4.89(t,J＝5.0Hz,2H),3.43(br s,1H)。LCMS(ESI):m/z 379.2(M+H) ⁺ 。

Example 12 (reverse coupling procedure):

step 1:3-fluoro-5- (3- (methoxy-d 3) phenyl) pyridin-2-amine (12 a)

To 5-bromo-3-fluoropyridin-2-amine (400 mg,2.09 mmol) in 1,4-dioxane (5 mL) and H ₂ To a solution of (3- (methoxy-d 3) phenyl) boronic acid (389 mg,2.51 mmol), cs, was added in O (0.5 mL) ₂ CO ₃ (2.4 g,6.27 mmol) and Pd (dppf) Cl ₂ (40 mg,0.11 mmol). The mixture was heated to 90℃under N ₂ Stirred for 2 hours and cooled to room temperature. The organic layer was separated, concentrated and purified by FCC (PE: ea=10:1) to give compound 12a as a yellow solid. LCMS (ESI) M/z 222.0 (M+H) ⁺ 。

Step 2:2- ((3-fluoro-5- (3- (methoxy-d 3) phenyl) pyridin-2-yl) aminomethyl) cyclopent-1-ene-1-carboxylic acid (12)

Target molecule 12 is obtained by reacting compound 12a as described in example 6, step 4. ¹ H-NMR(500MHz,MeOD)δ8.50(br s,1H),7.99(d,J＝9.0Hz,1H),7.41(t,J＝8.0Hz,1H),7.25-7.21(m,2H),6.99(dd,J＝8.5,2.0Hz,1H),2.97-2.93(m,2H),2.86-2.83(m,2H),2.03-1.97(m,2H)。LCMS(ESI):m/z 360.1(M+H) ⁺ 。

Examples 12/1 to 12/6:

the following examples were prepared analogously to example 12 above using the appropriate building blocks shown below.

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Example 13:

step 1:(3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) di-tert-butyl iminodicarbonate (13 a)

Target compound 13a was prepared by treating compound 9b with di-tert-butyl dicarbonate-containing DMF with DMAP as a catalyst, similar to that described in WO 2008/018426.

Step 2:(3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) carbamic acid tert-butyl ester (13 b)

Similar to chem.Commun.2018;54:4589 by the presence of CH at 0 ℃ as described in the specification ₂ Cl ₂ The target compound 13b was prepared by treating the compound 13a with trifluoroacetic acid.

Step 3:(3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) (methyl) carbamic acid tert-butyl ester (13 c)

Similar to j.am.chem.soc.2002;124:8206, the target compound 13c is prepared by treating compound 13b with lithium bis (trimethylsilyl) amide and MeI.

Step 4:3,5-difluoro-3 '- (methoxy-d 3) -N-methyl- [1,1' -biphenyl]-4-amine (13 d)

The target compound 13d was prepared by deprotecting compound 13c with 4N HCl in dioxane, and treating under basic conditions.

Step 5:2- ((3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) (methyl) aminomethyl-cyclopent-1-ene-1-carboxylic acid (13)

The target compound 13 was prepared by coupling compound 13d with 1-cyclopentene-1,2-dicarboxylic anhydride, similarly as described above. LCMS (ESI) M/z 391.1 (M+H) ⁺ 。

Example 14:

step 1:(3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) glycine methyl ester (14 a)

Target compound 14a can be prepared by treating compound 9b with methyl 2-bromoacetate.

Step 2:2- ((3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl)]-4-yl) (2-methoxy-2-oxoethyl) aminomethyl) cyclopent-1-ene-1-carboxylic acid (14)

The target compound 14 can be prepared by coupling compound 14a with 1-cyclopentene-1,2-dicarboxylic anhydride, similar to that described above.

Example 15:2- ((3,5-difluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl ] -4-yl) (2-hydroxyethyl) aminomethyl) cyclopent-1-ene-1-carboxylic acid (15)

The target compound 15 may be prepared by reducing the compound 14a with, for example, lithium borohydride.

Example 99:2- ((3-fluoro-3 '- (methoxy-d 3) - [1,1' -biphenyl ] -4-yl) aminomethyl) cyclopent-1-ene-1-carboxylic acid-3,3,4,4,5,5-d 6

Dimethyl azelate-d 8 can be obtained by double esterifying azelaic acid-d 8 (CAS number 52089-65-3) with MeOH. The diester may be cyclized as described in WO2009/140279 to give methyl 2-hydroxycyclopent-1-ene-1-carboxylate-3,3,4,4,5,5-d 6 from which the corresponding triflate may be prepared. Such as hetercycles 2009;77:179, the mono-acid cyclopent-1-en-1,2-dicarboxylic acid-d 6 can be obtained by palladium-catalyzed reaction with sodium formate, which can be coupled to compound 1b to give the target molecule.

Examples 100/1 to 100/13:

the following examples can be prepared analogously to the examples described above using the appropriate building blocks shown below.

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Examples 101/1 to 101/16:

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Example 200: human DHODH inhibition assay

Such as j.med.chem.2006;49:1239, in vitro inhibition of hDHODH was measured using an N-terminally truncated recombinant hDHODH enzyme. Briefly, the hdhaodh concentration is adjusted in such a way that an average slope of about 0.2AU/min is used as a positive control (e.g., no inhibitor). The standard assay mixture contained 60. Mu.M 2,6-dichloroindoxyl, 50. Mu.M decyl ubiquinone, and 100. Mu.M dihydroorotic acid. hDHODH enzyme was added with or without at least six different concentrations of compound and measured in 50mM TrisHCl, 150mM KCl and 0.1% Triton X-100 at pH 8.0 and 30 ℃. The reaction was started by adding dihydroorotic acid and absorbance was measured at 600nm for 2 minutes. To determine IC ₅₀ Values, each data point record in triplicate. To determine the inhibition constant K _i Determination of K of DHO and decyl ubiquinone _M Values. Thereafter, depending on the compound's IC in DMSO ₅₀ Values, they were diluted into dilution series. The dilution was: 0 x IC ₅₀ 、1/4×IC ₅₀ 、1/2×IC ₅₀ 、1×IC ₅₀ 、2×IC ₅₀ 、4×IC ₅₀ . Furthermore, in other dilution series in which DHO and decyl ubiquinone were measured separately, the substrate concentrations of DHO and decyl ubiquinone were varied to 1/4 XK _M 、1/2×K _M 、1×K _M 、2×K _M 、4×K _M . Each data point is recorded in duplicate.

K of the embodiment of the invention _i The values are in the range of the matching pair not deuterated (example C26 of WO 2003/006425):

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IC of human DHODH assay as described herein ₅₀ The range is as follows: +++:<100nM; ++:100nM to<1. Mu.M; +:1 mu M to<10μΜ；0：≥10μΜ。

As shown above, DHODH inhibition by deuterated analogs (i.e., 1, 2, and 6) is unaffected compared to the non-deuterated counterpart pair (example C26 of WO 2003/006425). The same applies to example 4, where the reporting IC of the non-deuterated matching pair ₅₀ 7nM (Bioorg. Med. Chem. Lett.2005; 15:4854).

Example 201: particle stability

Examples 1 and 2 and the non-deuterated pair of matches (example C26 of WO 2003/006425) were incubated with three different batches of male Rat Liver Microparticles (RLM) and Human Liver Microparticles (HLM), respectively, for a period of 60 minutes. Metabolite conversion was monitored by HPLC-MS/MS. Verapamil was used as a positive control. Intrinsic clearance was calculated from residual compound values measured at 0, 10 min, 30 min and 60 min (in duplicate). The data points at 60 minutes are as follows:

As exemplified in examples 1 and 2, the intrinsic clearance of the compounds of the invention in rats and human microparticles can be reduced by deuteration compared to the non-deuterated counterpart. Reducing intrinsic clearance is beneficial because it increases the residence time of the drug in the body.

The example 1 and example 2 and the non-deuterated pair of matches (example C26 of WO 2003/006425) were incubated with three identical different batches of Rat Liver Microparticles (RLM) and Human Liver Microparticles (HLM) for a period of 60 minutes (in duplicate, i.e. measurement 1 and measurement 2). Conversion of the parent to the demethylated metabolite was monitored and quantified by HPLC-MS/MS (peak area of mass peak) to give the percentage of the demethylated metabolite relative to the original parent (% of the original parent). Using this data, the mean and Standard Deviation (SD) were calculated.

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As exemplified in examples 1 and 2, methoxy degradation in rat microparticles to form hydroxyl metabolites can be reduced by selective deuteration compared to the non-deuterated counterpart (example C26).

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By selective deuteration, methoxy degradation in human microparticles to form hydroxyl metabolites can also be reduced, as exemplified in example 1 and example 2, compared to the non deuterated matching pair (example C26).

Example 202: rat pharmacokinetics

In 3 male rats and 3 female rats (strain Han Wistar,8 weeks old), the pharmacokinetics of deuterated compounds of the invention were evaluated after oral or intravenous cassette administration to assess oral bioavailability. The jugular vein of the rat was cannulated (2-3 days prior to blood collection). At each indicated time point (0 hours, 1 hour, 2 hours, 4 hours, 8 hours and 24 hours after dosing), 100 μl of blood was collected into Li-heparin tubes, stored on ice until centrifugation (10 minutes at 3000g, 4 ℃) plasma was prepared within 45 minutes after collection, frozen at-20 ℃ and stored at that temperature until processing was performed for LC-MS analysis. The data obtained are as follows:

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the unhanded compound vedoraforolamol (comparative example C26) itself already has a fairly good bioavailability. The bioavailability can be further improved by selective deuteration (example 2), which can be attributed to reduced metabolism.

Example 203: mouse pharmacokinetics

In 3 male mice and 3 female mice (C57 BL/6J,8 weeks old), the pharmacokinetics of the compounds of the present invention were evaluated after oral cassette administration. The dosage was 5mg/kg, the application volume was 5mL/kg, and the vehicle was 5% Solutol, 95% NaCl solution (0.9% physiological saline concentration). At each indicated time point (0 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours post-administration), 20 μl of whole blood was collected from the tail vein into Li-heparin tubes, sampled for 1-2 minutes, frozen on dry ice and stored at-20 ℃ until processing for LC-MS analysis. The data obtained are as follows:

Comparative example C26, which was not deuterated, also had a lower C _max And AUC values, which can be significantly improved by selective deuteration (example 1).

Example 204: antiviral Activity against SARS-CoV-2

Viral replication assays (YFP) and cell viability assays are already in pathens 2021;10:1076, and are applied to the compounds of the present invention, the following results are obtained:

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EC of SARS-CoV-2 assay as described herein ₅₀ The range is as follows: +++:<10. Mu.M; ++:10 mu M to<25. Mu.M; +:25 mu M to<50μΜ；0：≥50μΜ。

Example 205: synergistic antiviral Activity against SARS-CoV-2 together with nucleoside analogues

The synergistic potential of example 9 together with the nucleotide analogue EIDD-1931 (CAS: 3258-02-4) was evaluated.

Methods for combination drug evaluation by viral replication inhibition assays have been disclosed in Pathogens 2021;10:1076.Caco-2 cells were cultured in 96-well plates at 25000 cells/well, infected with SARS-CoV-2d6-YFP at an MOI of 0.003, and isolated from the corresponding 4 XEC using example 9, EIDD-1931 or a pharmaceutical combination ₅₀ The concentration of the individual compounds begins to process. Viral replication was determined 30 hours after infection (p.i.) by quantitative fluorescence detection of virus-driven YFP expression in fixed cells. The viral replication inhibition profile measured by virally encoded YFP reporter gene expression is presented in the bar graph of four replicates (mean ± SD). Such as int.j.mol.sci.2021;22:575, the combined drug evaluation was calculated by using the CompuSyn algorithm.

Representative experiments are shown in figure 1. The compound of example 9, when combined with the nucleoside analog EIDD-1931 (CAS: 3258-02-4), showed a synergistic antiviral effect against SARS-CoV-2.

Claims

1. A compound of formula (I):

wherein residue-NR on ring B ² In 1,4-orientation relative to ring C,

Wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 1 to 4 substituents independently selected from the group consisting of: halogen, -CN, -NO ₂ Oxo, C _1-4 -alkyl, C _0-6 -alkylene-OR ³¹ 、C _0-6 Alkylene- (3-6 membered cycloalkyl) radicals, C _0-6 Alkylene- (3-6 membered heterocycloalkyl), C _0-6 -alkylene-S (=o) _n (＝NR ³³ ) _m R ³¹ 、C _0-6 -alkylene-NR ³¹ S(＝O) _x (＝NR ³³ ) _y R ³¹ 、C _0-6 -alkylene-S (=o) _x (＝NR ³³ ) _y NR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ S(＝O) _x (＝NR ³³ ) _y NR ³¹ R ³² 、C _0-6 -alkylene-CO ₂ R ³¹ 、C _0-6 -alkylene-O-COR ³¹ 、C _0-6 -alkylene-CONR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ -COR ³¹ 、C _0-6 -alkylene-NR ³¹ -CONR ³¹ R ³² 、C _0-6 -alkylene-O-CONR ³¹ R ³² 、C _0-6 -alkylene-NR ³¹ -CO ₂ R ³¹ 、C _0-6 Alkylene groupradical-NR ³¹ R ³² ，

R ¹ selected from H and D;

R ² selected from H and C _1-6 -an alkyl group, which is a group,

n, m, x, y are independently selected from 0 to 2;

2. A compound of formula (I) or a solvate or pharmaceutically acceptable salt thereof according to claim 1, wherein

R ¹ Is H and R ² Is H.

3. A compound of formula (I) according to claim 1 or 2, whereinSelected from the group consisting of

4. A compound of formula (I) according to any one of claims 1 to 3, wherein-NR ² B is selected from

5. A compound of formula (I) according to any one of claims 1 to 4, wherein

C is phenyl, pyrazolone or thiotezate,

x is selected from D, F, cl, -CN, OH, C _1-4 -alkyl, O-C _1-4 -alkyl, fluoro-C _1-4 -alkyl, O-C _1-4 -alkyl, optionally substituted with deuterium, having one or more hydrogen atoms.

6. A compound of formula (I) according to any one of claims 1 to 5, whereinSelected from the group consisting of

7. A compound of formula (I) according to any one of claims 1 to 6, whereinSelected from the group consisting of

8. A compound of formula (I) according to any one of claims 1 to 7, wherein R ¹ Is H and R ² Is H;

Selected from->

-NR ² B is selected from

Selected from->

9. A compound of formula (I) according to any one of claims 1 to 8, selected from the group consisting of

Or a solvate or pharmaceutically acceptable salt thereof.

10. A compound according to any one of the preceding claims for use as a medicament.

11. A compound according to any one of claims 1 to 10 for use in the prevention and/or treatment of a disease, disorder, therapeutic indication or medical condition suitable for treatment with a DHODH inhibitor.

12. The compound for use according to claim 11, wherein said disease, disorder, therapeutic indication or medical condition is selected from the group consisting of rheumatism, acute immune disorders, autoimmune diseases, diseases caused by malignant cell proliferation, inflammatory diseases, diseases caused by protozoal infections in humans and animals, diseases caused by viral infections and pneumocystis carinii, fibrosis, uveitis, rhinitis, asthma, transplantation or arthrosis.

13. A compound for use according to claim 12, wherein the disease, disorder or therapeutic indication is selected from graft versus host and host versus graft response, rheumatoid arthritis, multiple sclerosis, amyotrophic lateral sclerosis, lupus erythematosus, inflammatory bowel disease, cancer, covd-19, influenza, ulcerative colitis, crohn's disease, primary sclerosing cholangitis and psoriasis.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier or excipient.

15. The pharmaceutical composition of claim 14, further comprising one or more additional therapeutic agents selected from the group consisting of antiviral agents, anti-inflammatory agents, immunosuppressants and/or immunomodulators, compounds of the family, non-family anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.