# US 11,028,054 B2 · 1, 4, 6-trisubstituted-2-alkyl-1H-benzo[d]imidazole derivatives as dihydroorotate oxygenase inhibitors

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- Number: US 11,028,054 B2
- Document ID: US11028054B2
- Status: Granted
- Kind: B2
- Application number: 16/488,151
- Filed: 2018-02-23
- Published: 2020-05-07
- Granted: 2021-06-08
- Earliest claimed: 2017-02-24
- Assignees: Merck Patent GmbH
- Applicants: Merck Patent GmbH
- Inventors: Siva Sanjeeva Rao Thunuguntla; Subramanya Hosahalli; Sunil Kumar Panigrahi; Matthias Schwarz; Michael Arit
- Web page: https://patentgrep.com/patent/US11028054B2

## CPC

- C07D 235/24: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- C07D 235/08: Radicals containing only hydrogen and carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 417/10: linked by a carbon chain containing aromatic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides 1, 4, 6-trisubstituted-2-alkyl-1H-benzo[d]imidazole derivatives as dihydroorotate oxygenase inhibitor compounds of formula (I), which may be therapeutically useful as DHODH inhibitors, in which R1 to R3 and ‘m’ have the meanings given in the specification, and pharmaceutically acceptable salts or stereoisomer thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting DHODH. The present invention also provides methods for synthesizing 1, 4, 6-trisubstituted-2-alkyl-1H-benzo[d]imidazole derivatives of formula (I). The present invention also provides pharmaceutical formulations comprising at least one of the DHODH inhibitor compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable salt, solvate, tautomer, hydrate, stereoisomer and mixture of isomers, or N-oxide thereof;
wherein;
R1 is hydrogen or linear or branched C1-C6 alkyl;
R2 is an optionally substituted Cb, an optionally substituted Het or —O—(CH2)pCb′; wherein the optional substituent, at each occurrence, is independently selected from one or more occurrences of R4;
R3 is hydrogen, halogen, linear or branched C1-C6 alkyl or —OR5;
R4 is independently selected from hydrogen, halogen, linear or branched C1-C6 alkyl, —(CH2)pO(CH2)qR7, —(CH2)pS(═O)xR5, —C(R5)═NOR5, —(CH2)pHet′ and —(CH2)pNR5(CH2)qR6;
R5 is independently selected from hydrogen and linear or branched C1-C6 alkyl;
R6 is independently selected from hydrogen, linear or branched C1-C6 alkyl, —(CO)Het, Cb′, Het′, —CF3, —C≡CR5, —N(R5)2, —S(═O)xR5 and OR5;
R7 is independently selected from hydrogen, linear or branched C1-C6 alkyl, Cb′, Het′, —CF3, —C≡CR5, —N(R5)2 or —S(═O)xR5;
Cb and Cb′ independently represents a monocyclic, a fused or non-fused bicyclic, saturated, unsaturated or aromatic carbocyclic ring system having 3 to 14 carbon atoms; wherein the Cb and Cb′ are optionally substituted with ‘n’ occurrences of R7;
Het and Het′ independently represents a 3- to 14-membered, monocyclic, a fused or non-fused bicyclic, saturated, unsaturated or aromatic heterocyclic ring system having at least 1 to 4 heteroatom or heterogroup selected from N, O, S, CO, NH, SO and SO2; wherein the Het and Het′ are optionally substituted with ‘n’ occurrences of R8;
R8, at each occurrence, is independently selected from halogen, hydroxy, oxo and linear or branched C1-C6 alkyl;
‘m’ is 0 to 4; ‘n’, ‘p’ and ‘q’ independently represents 0 to 3; and ‘x’ is 0 to 2.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein the compound is represented by formula (IA);
or a pharmaceutically acceptable salt or a stereoisomer thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein the compound is represented by formula (IB);
or a pharmaceutically acceptable salt or a stereoisomer thereof.

### Claim 4 (depends on 2)

The compound according to claim 2, wherein R1 is hydrogen.

### Claim 5 (depends on 1)

The compound according to claim 1, with all tautomeric forms of formula (Ia) and (Ia′) when R1 is hydrogen;
or a pharmaceutically acceptable salt or a stereoisomer thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R2 is an optionally substituted phenyl; wherein the optional substituent, at each occurrence, is independently selected from one or more occurrences of R4.

### Claim 7 (depends on 2)

The compound according to claim 2, wherein R4 is independently selected from hydrogen, halogen, linear or branched C1-C6 alkyl, —(CH2)pHet′, —(CH2)pNR5(CH2)qR6 and —(CH2)pO(CH2)qR7; wherein R5 is hydrogen; and R6 and R7 independently represents Cb′ and Het′.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein Cb′ represents phenyl or cyclopropyl; and Het′ denotes piperidine, morpholine, 3-fluoro pyrrolidine, or thiomorpholine 1,1-dioxide.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R3 is hydrogen or halogen.

### Claim 10

A compound, or a pharmaceutically acceptable salt or a stereoisomer thereof, selected from one or more of the following:
Example
No
IUPAC names
1.
6-([1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid;
2.
6-(3',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
3.
6-(3',4'-difluoro-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
4.
6-(2',3'-difluoro-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
5.
6-(2'-fluoro-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
6.
6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
7.
2-methyl-6-(4-(pyridin-3-yl)phenyl)-1H-
benzo[d]imidazole-4-carboxylic acid;
8.
6-(3'-fluoro-[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic
acid.;
9.
2-methyl-6-(4-(pyridin-4-yl)phenyl)-1H-
benzo[d]imidazole-4-carboxylic acid;
10.
6-(3'-methoxy-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
11.
2-methyl-6-(3'-(trifluoromethoxy)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid;
12.
6-(2',5'-difluoro-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
13.
2-methyl-6-(4'-(trifluoromethoxy)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid;
14.
6-(4'-methoxy-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
15.
6-(3'-(benzyloxy)-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
16.
6-(3'-hydroxy-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
17.
6-(2'-(benzyloxy)-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
18.
6-(2'-methoxy-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
19.
6-(4'-(benzyloxy)-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
20.
6-(4'-hydroxy-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
21.
6-(2'-fluoro-3'-methoxy-[1,1'-biphenyl]-4-yl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
22.
6-(3'-(benzyloxy)-5'-fluoro-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid;
23.
6-(2'-hydroxy-[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid;
24.
2-methyl-6-(3'-methyl-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid;
25.
2-methyl-6-(2'-methyl-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid;
26.
2-methyl-6-(4'-(piperidin-1-ylmethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
27.
6-(4'-((isopropylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
28.
2-methyl-6-(4'-(pyrrolidin-1-ylmethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
29.
2-methyl-6-(4'-(thiomorpholinomethyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
30.
6-(4'-((3,3-difluoropiperidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
31.
2-methyl-6-(3'-(piperidin-1-ylmethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
32.
2-methyl-6-(3'-(pyrrolidin-1-ylmethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
33.
2-methyl-6-(3'-(thiomorpholinomethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid;
34.
6-(3'-((isopropylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
35.
2-methyl-6-(3'-(morpholinomethyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
36.
6-(3'-((1,1-dioxidothiomorpholino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
37.
6-(3'-((3,3-difluoropiperidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
38.
6-(3'-((dipropylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
39.
6-(3'-((tert-butylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
40.
6-(3'-((cycloheptylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
41.
6-(3'-((3-hydroxyazetidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
42.
2-methyl-6-(2'-(piperidin-1-ylmethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
43.
6-(2'-((isopropylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
44.
2-methyl-6-(2'-(thiomorpholinomethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
45.
2-methyl-6-(2'-(morpholinomethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
46.
2-methyl-6-(2'-(pyrrolidin-1-ylmethyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
47.
6-(2'-((1,1-dioxidothiomorpholino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
48.
6-(2'-((cyclopropylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
49.
6-(2'-((dimethylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
50.
6-(2'-((3,3-difluoropiperidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
51.
6-(2'-((cycloheptylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
52.
2-methyl-6-(2,3,5,6-tetrafluoro-[1,1'-biphenyl]-
4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid;
53.
2-methyl-6-(2,3,5,6-tetrafluoro-2'-(piperidin-
1-ylmethyl)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
54.
2-methyl-6-(2,3,5,6-tetrafluoro-2'-
(thiomorpholinomethyl)-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
55.
2-methyl-6-(2,3,5,6-tetrafluoro-2'-
((isopropylamino)methyl)-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
56.
2-methyl-6-(2,3,5,6-tetrafluoro-3'-(piperidin-
1-ylmethyl)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
57.
2-methyl-6-(2,3,5,6-tetrafluoro-3'-
(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
58.
2-methyl-6-(2,3,5,6-tetrafluoro-3'-
(pyrrolidin-1-ylmethyl)-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic acid;
59.
2-methyl-6-(2,3,5,6-tetrafluoro-3'-
((isopropylamino)methyl)-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
60.
6-(3'-((cyclopropylamino)methyl)-2,3,5,6-
tetrafluoro-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
61.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-(piperidin-1-
ylmethyl)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
62.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-(pyrrolidin-
1-ylmethyl)-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
63.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-
(thiomorpholinomethyl)-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
64.
6-(4'-((3,3-difluoropiperidin-1-yl)methyl)-
2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-
2-methyl-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
65.
6-(4'-((1,1-dioxidothiomorpholino)methyl)-
2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-
yl)-2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
66.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-
((isopropylamino)methyl)-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
67.
6-(4-(2,5-dimethyl-1H-pyrrol-1-yl)-
2,3,5,6-tetrafluorophenyl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid;
68.
6-([1,1'-biphenyl]-4-yl)-1,2-dimethyl-1H-
benzo[d]imidazole-4-carboxylic acid;
69.
6-(4-(benzyloxy)phenyl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid;
70.
2-methyl-6-(4'-(piperidin-4-ylmethoxy)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
71.
2-methyl-6-(4'-(2-(piperidin-4-yl)ethoxy)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
72.
2-methyl-6-(3'-(piperidin-4-ylmethoxy)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
73.
2-methyl-6-(3'-(piperidin-4-yloxy)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
74.
2-methyl-6-(4'-(2-morpholinoethoxy)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
75.
2-methyl-6-(3'-(2-(piperidin-4-yl)ethoxy)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
76.
2-methyl-6-(3'-(2-(tetrahydro-2H-pyran-4-
yl)ethoxy)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
77.
(S)-2-methyl-6-(3'-(pyrrolidine-2-
carboxamido)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
78.
2-methyl-6-(3'-(piperidine-4-carboxamido)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
79.
2-methyl-6-(2'-(methylsulfonyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
80.
2-methyl-6-(3'-(methylsulfonyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid;
81.
2-methyl-6-(4'-(methylsulfonyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
82.
6-(2'-((benzylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
83.
6-(4'-(methoxymethyl)-[1,1'-biphenyl]-4-
yl)-2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
84.
2-methyl-6-(2,3,5,6-tetrafluoro-3'-
(morpholinomethyl)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
85.
2-methyl-6-(4'-((methylsulfonyl)methyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid;
86.
2-methyl-6-(4'-((methylthio)methyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid;
87.
6-(3'-((benzylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid;
88.
6-(2'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
89.
2-methyl-6-(4'-methyl-[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid;
90.
6-(3'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
91.
6-(4'-((benzylamino)methyl)-2,3,5,6-tetrafluoro-
[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
92.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-(methylthio)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid;
93.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-(methylsulfonyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid;
94.
6-(2'-((4-hydroxypiperidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
95.
(R)-6-(3'-((3-hydroxypyrrolidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
96.
2-methyl-6-(4'-(piperidin-1-yl)-[1,1'-biphenyl]-
4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
97.
2-methyl-6-(3'-((4-methylpiperidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
98.
6-(3'-((cyclopentylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
99.
6-(3'-(((cyclopropylmethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
100.
6-(3'-((4-hydroxypiperidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
101.
6-(4'-(hydroxymethyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
102.
6-(2'-((3-hydroxyazetidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid;
103.
6-(2'-((dipropylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid;
104.
6-(2'-(((2-methoxyethyl)amino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid;
105.
2-methyl-6-(2'-((2-oxoazepan-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-1H-benzo[d]
imidazole-4-carboxylic acid;
106.
6-(2'-((tert-butylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
107.
(R)-6-(2'-((3-hydroxypyrrolidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
108.
2-methyl-6-(2'-((4-methylpiperidin-1-
yl)methyl)-[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
109.
2-methyl-6-(2'-((2-oxopyrrolidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
110.
6-(2'-(((cyclopropylmethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
111.
6-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
112.
6-(3'-(((2-methoxyethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
113.
2-methyl-6-(3'-((prop-2-yn-1-ylamino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
114.
2-methyl-6-(3'-(((2-(methylsulfonyl)ethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
115.
(R)-6-(3'-((3-fluoropyrrolidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
116.
2-methyl-6-(2'-(((l-methylpiperidin-4-yl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
117.
(R)-6-(2'-((3-fluoropyrrolidin-1-yl)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
118.
6-(2'-((cyclohexylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
119.
6-(2'-((cyclohexyl(methyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid;
120.
(R)-2-methyl-6-(2,3,5,6-tetrafluoro-4'-((2-
hydroxypyrrolidin-1-yl)methyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-carboxylic acid;
121.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-
((4-methylpiperidin-1-yl)methyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
122.
6-(4'-(((cyclopropylmethyl)amino)methyl)-
2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-
yl)-2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
123.
(R)-2-methyl-6-(2,3,5,6-tetrafluoro-4'-((2-
fluoropyrrolidin-1-yl)methyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
124.
6-(3'-(((cyclohexylmethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
125.
6-(3'-(((3-(dimethylamino)propyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
126.
6-(3'-((diisobutylamino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
127.
2-methyl-6-(2,3,5,6-tetrafluoro-4'-((prop-2-
yn-1-ylamino)methyl)-[1,1'-biphenyl]-
4-yl)-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
128.
6-(4'-((cyclohexylamino)methyl)-2,3,5,6-
tetrafluoro-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
129.
6-(2'-(((cyclohexylmethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
130.
6-(2'-(((4-hydroxycyclohexyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
131.
2-methyl-6-(2'-((prop-2-yn-1-ylamino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
132.
(E)-6-(3'-((methoxyimino)methyl)-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid;
133.
6-(2'-(((3-(dimethylamino)propyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
134.
6-(2-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
135.
2-methyl-6-(3'-(((2,2,2-trifluoroethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
136.
2-methyl-6-(3'-(((3,3,3-trifluoropropyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
137.
6-(3'-((1,1-dioxidothiomorpholino)methyl)-
2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-
yl)-2-methyl-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
138.
6-(4-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
139.
2-methyl-6-(4-(3-methyl-1H-pyrazol-1-
yl)phenyl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
140.
6-(2'-((diisobutylamino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid;
141.
2-methyl-6-(2'-(((2-(piperidin-1-yl)ethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid;
142.
2-methyl-6-(2'-(((3,3,3-trifluoropropyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid;
143.
(E)-6-(3'-((ethoxyimino)methyl)-[1,1'-biphenyl]-
4-yl)-2-methyl-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
144.
6-(4-(4,5-dimethyloxazol-2-yl)phenyl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
145.
6-(2',6'-dimethyl-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
146.
6-(4'-(((3-(dimethylamino)propyl)amino)methyl)-
2,3,5,6-tetrafluoro-[1,1'-
biphenyl]-4-yl)-2-methyl-1H-benzo[d]imidazole-
4-carboxylic acid.2,2,2-
trifluoroacetic acid;
147.
2-methyl-6-(2,3,5,6-tetrafluoro-4-
(morpholinomethyl)phenyl)-1H-benzo[d]
imidazole-4-carboxylic acid.2,2,2-trifluoroacetic acid;
148.
(R)-2-methyl-6-(2,3,5,6-tetrafluoro-3'-((3-
fluoropyrrolidin-1-yl)methyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
149.
(R)-2-methyl-6-(2,3,5,6-tetrafluoro-3'-((3-
hydroxypyrrolidin-1-yl)methyl)-[1,1'-
biphenyl]-4-yl)-1H-benzo[d]imidazole-4-
carboxylic acid.2,2,2-trifluoroacetic acid;
150.
6-(2'-fluoro-6'-(pyrrolidin-1-ylmethyl)-
[1,1'-biphenyl]-4-yl)-2-methyl-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
151.
6-(3-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-
2-methyl-1H-benzo[d]imidazole-4-
carboxylic acid;
152.
2-methyl-6-(2'-(((3-morpholinopropyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-1H-
benzo[d]imidazole-4-carboxylic acid.2,2,2-
trifluoroacetic acid;
153.
6-(2'-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
154.
6-(2'-((3,3-difluoropiperidin-1-yl)methyl)-
2,3,5,6-tetrafluoro-[1,1'-biphenyl]-4-yl)-
2-methyl-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid;
155.
6-(3'-((cyclohexylamino)methyl)-2,3,5,6-
tetrafluoro-[1,1'-biphenyl]-4-yl)-2-
methyl-1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid; and
156.
2-methyl-6-(2'-(((2-(methylsulfonyl)ethyl)amino)methyl)-
[1,1'-biphenyl]-4-yl)-
1H-benzo[d]imidazole-4-carboxylic
acid.2,2,2-trifluoroacetic acid.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, hydrate, stereoisomer and mixture of isomers, or N-oxide thereof, in admixture with at least one pharmaceutically acceptable carrier or excipient or mixtures thereof in all ratios.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R2 is an optionally substituted Het selected from pyrrole, pyrazole, pyridyl, and isoxazole; wherein the optional substituent, at each occurrence, is independently selected from one or more occurrences of R4.

### Claim 13 (depends on 1)

A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, hydrate, stereoisomer and mixture of isomers, or N-oxide thereof, wherein the subject has leukemia.

### Claim 14 (depends on 1)

A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, hydrate, stereoisomer and mixture of isomers, or N-oxide thereof, wherein the subject has multiple sclerosis or rheumatoid arthritis.

### Claim 15 (depends on 1)

A method of treating a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, hydrate, stereoisomer and mixture of isomers, or N-oxide thereof, wherein the subject has a dihydroorotate dehydrogenase mediated disease or disorder.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the dihydroorotate dehydrogenase mediated disease or disorder is an autoimmune disorder or condition associated with an overactive immune response.