# US 9,040,565 B2 · 1H-benzimidazole-5-carboxamides as anti-inflammatory agents

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- Number: US 9,040,565 B2
- Document ID: US9040565B2
- Status: Granted
- Kind: B2
- Application number: 13/119,835
- Filed: 2009-09-25
- Published: 2012-05-17
- Granted: 2015-05-26
- Earliest claimed: 2008-09-25
- Assignees: Orexo AB
- Applicants: Roland Pfau; Kirsten Arndt; Henri Doods; Norbert Hauel; Klaus Klinder; Raimund Kuelzer; Juergen Mack; Dirk Stenkamp
- Inventors: Roland Pfau; Kirsten Arndt; Henri Doods; Norbert Hauel; Klaus Klinder; Raimund Kuelzer; Juergen Mack; Dirk Stenkamp
- Web page: https://patentgrep.com/patent/US9040565B2

## CPC

- C07D 235/30: Nitrogen atoms not forming part of a nitro radical
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/24: of the sex hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 263/58: 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
- C07D 277/82: Nitrogen atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There are provided compounds of formula (I), wherein R1, R6, R8, Q2, Q3, Q3a, Q4, L and A have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of a member of the MAPEG family is desired and/or required, and particularly in the treatment of inflammation and/or cancer.

## Claims

### Claim 1

A compounds of formula Ia, Ib or Ic:
in which
R1 represents C1-3 alkyl optionally substituted by one or more fluoro atoms, C3-6 cycloalkyl, fluoro, chloro, bromo;
R2 represents hydrogen, C1-3 alkyl optionally substituted by one or more fluoro atoms, C3-6 cycloalkyl, fluoro, chloro, bromo;
R3, R3a and R4 independently represent hydrogen, fluoro, chloro, bromo, C1-3 alkyl optionally substituted by one or more fluoro atoms;
R6 represents hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from fluoro, —N(Ry1)Ry2, —N(Ry3)—C(O)—Ry4, —N(Ry5)—S(O)2—Ry6, —C(O)ORy7, —C(O)N(Ry8)Ry9, —ORy10, —S(O)2Ry11 and a 4- to 6-membered heterocycloalkyl group containing two or one heteroatom(s) selected from oxygen and nitrogen;
R8 independently represents hydrogen, fluoro, chloro, bromo, —ORy10 or C1-3 alkyl optionally substituted by one or more fluoro atoms;
A represents phenyl, 2-pyridyl, C3-10cycloalkyl, C1-12 linear or branched alkyl, all of which are optionally substituted by one or more substituents selected from R9;
R9 represents on each occasion when used herein: halo, —CN, —N(Ry1)Ry2, —N(Ry3)—C(O)—Ry4, —N(Ry5)—S(O)2—Ry6, —C(O)ORy7, —C(O)N(Ry8)Ry9, —ORy10, —S(O)m—Ry11, —S(O)2O—Ry12, —S(O)2N(Ry13)Ry14 and/or —C(O)Ry15, C1-6alkyl optionally substituted by one or more substituents selected from halo, —CN, —N(Ry1)Ry2, —N(Ry3)—C(O)—Ry4, —N(Ry5)—S(O)2—Ry6, —C(O)ORy7, —C(O)N(Ry8)Ry9, —ORy10, —S(O)m—Ry11, —S(O)2O—Ry12, —S(O)2N(Ry13)Ry14 and/or —C(O)Ry15;
aryl or heteroaryl, which latter two groups are optionally substituted by one or more groups selected from C1-7 alkyl optionally substituted by one or more substituents selected from fluoro and —ORx2; halo; —CN and/or —O—C1-7 alkyl optionally substituted by one or more fluoro atoms; or
any two R9 substituents,
when attached to the adjacent atoms of the A group and,
in the case where the R9 substituents are attached to a non-aromatic A group,
when attached to the same atoms,
may be linked together to form, together with the essential atoms of the A group to which the relevant R9 substituents are necessarily attached, a further 3- to 8-membered ring, optionally containing a further one or two heteroatoms, and which further ring optionally contains one or two unsaturations and which is optionally substituted by one or more C1-3 alkyl and/or ═O substituents;
each Ry4, Ry6, Ry11 and Ry15:
independently represent C1-4 alkyl;
and
each Rx2, Ry1, Ry2, Ry3, Ry5, Ry7, Ry8, Ry9, Ry10, Ry12, Ry13,and Ry14 :
independently represent hydrogen or C1-4 alkyl optionally substituted by one or more substituents selected from halo atoms and —OC1-2-alkyl; or
any two of these groups, when attached to the same nitrogen atom, that is Ry1 and Ry2, Ry8 and Ry9, or Ry13 and Ry14, may, together with that nitrogen atom to which they are necessarily attached, be linked together to form a 3- to 8-membered ring, which ring is optionally containing one or two further nitrogen or oxygen heteroatoms and optionally containing one or two double bonds in the ring and optionally substituted by one or more C1-3 alkyl and/or ═O substituents,
with the proviso that: if R6 is hydrogen; and R8 independently are hydrogen, C1-3 alkyl optionally substituted with one or more fluoro atoms or —ORy10 represents C1-7 alkyl or cycloalkyl which latter two groups are optionally substituted with one or more fluoro atoms;
then A is not phenyl or 2-pyridyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2

A compound of formula Id, Ie or If:
in which
R1 represents chloro, bromo, fluoro, C1-3 alkyl which latter alkyl group is optionally substituted by one or more fluoro-atoms;
R2 represents hydrogen, chloro, bromo, fluoro, C1-3-alkyl which latter alkyl group is optionally substituted by one or more fluoro atoms;
R3, R3a and R4 independently represent hydrogen, chloro, bromo, fluoro, C1-3-alkyl which latter alkyl group is optionally substituted by one or more fluoro atoms;
R6 represents hydrogen; C1-4 alkyl optionally substituted by one or more fluoro atoms;
R8 represent hydrogen, fluoro, chloro, —O—C1-4 alkyl optionally substituted by one or more fluoro atoms;
A represents phenyl, 2-pyridyl, C3-10 cycloalkyl, C1-12 alkyl, all of which are optionally substituted by one or more substituents selected from R9;
R9 represents, on each occasion when used herein:
halo, —ORy10; C1-7 alkyl, cycloalkyl, which latter two groups are optionally substituted by one or more fluoro atoms; or
aryl, heteroaryl which latter two groups are optionally substituted by one or more substituents selected from halo; C1-7 alkyl, cycloalkyl which latter two groups are optionally substituted by one or more fluoro atoms; —O—C1-3 alkyl which latter group is optionally substituted by one or more fluoro atoms;
and
Ry10 represents hydrogen or C1-4 alkyl, optionally substituted by one or more substituents selected from halo atoms and —OC1-2 alkyl;
with the proviso that: if R6 is hydrogen and R8 is hydrogen or —O—C1-4 alkyl aptionally substituted with one or more fluoro atoms,
then A is not phenyl or 2-pyridyl;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compounds according to claim 1, which is selected from the following compounds or a pharmaceutically acceptable salt thereof:
Compound Compound Name
Number
409 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethylcyclohexyl)-1H-benzimidazole-6-carboxamide;
410 N-(4-Bromophenyl)-2-(3,5-dichloropyridin-4-ylamino)-1-methyl-1H-benzimidazole-5-carboxamide;
435 2-(3,5-dichloropyridin-4-ylamino)-N-(4,4-dimethylcyclohexyl)-1-methyl-1H-benzimidazole-5-carboxamide;
446 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethylcyclohexyl)-1H-benzimidazole-5-carboxamide;
467 2-(3,5-Dichloropyridin-4-ylamino)-1-methyl-N-(2-trifluoromethyl-benzyl)-1H-benzimidazole-5-carboxamide;
493 2-(3,5-Dichloropyridin-4-ylamino)-N-(2-trifluoromethyl-benzyl)-1H-benzimidazole-5-carboxamide;
520 N-(4-Bromophenyl)-2-(3-chloropyridin-4-ylamino)-1-methyl-1H-benzimidazole-5-carboxamide;
531 2-(2-Chloro-4-methylpyridin-3-ylamino)-N-(4,4-dimethylcyclohexyl)-1H-benzimidazole-5-carboxamide;
532 N-(4-Bromophenyl)-1-methyl-2-(3-trifluoromethyl-pyridin-4-ylamino)-1H-benzimidazole-5-carboxamide;
547 N-Cyclohexyl-2-(3,5-dichloropyridin-4-ylamino)-1-methyl-1H-benzimidazole-5-carboxamide;
553 2-(3,5-Dichloropyridin-4-ylamino)-1-methyl-N-((3-trifluoromethyl-pyridin-2-yl)methyl)-1H-benzimidazole-5-carboxamide;
565 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)methyl)-1H-benzimidazole-5-carboxamide;
567 N-(4-Bromophenyl)-1-methyl-2-(3-methylpyridin-4-ylamino)-1H-benzimidazole-5-carboxamide
660 2-(3,5-Dichloropyridin-4-ylamino)-N-(4-bromophenyl)-6-propoxy-1-methyl-1H-benzimidazole-5-carboxamide;
666 2-(3,5-Dichloropyridin-4-ylamino)-N-(4-bromophenyl)-6-(2-methoxy-ethoxy)-1-methyl-1H-benzimidazole-5-carboxamide;
667 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)-methyl)-6-ethoxy-1H-benzimidazole-5-carboxamide;
668 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)-methyl)-6-ethoxy-1-methyl-1H-benzimidazole-5-carboxamide;
669 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-ethoxy-1H-benzimidazole-5-carboxamide;
670 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-ethoxy-1-methyl-1H-benzimidazole-5-carboxamide;
671 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-(2-methoxy-ethoxy)-1-methyl-1H-benzimidazole-5-carboxamide;
672 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohexyl)-6-dimethylamino-1-methyl-1H-benzimidazole-5-carboxamide;
673 2-(3,5-Dichloro-pyridin-4-yl-amino)-6-fluoro-N-(4,4-dimethyl-cyclohex-1-yl)-1H-benzimidazole-5-carboxamide;
674 2-(3,5-Dichloropyridin-4-ylamino)-N-(4,4-dimethyl-cyclohex-1-yl)-6-fluoro-1-methyl-1H-benzimidazole-5-carboxamide;
675 2-(3,5-Dichloro-pyridin-4-yl-amino)-6-(2,2,2-trifluoro-ethoxy)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-1H-benzimidazole-5-carboxamide;
677 2-(3,5-Dichloropyridin-4-ylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-6-(2-fluoroethoxy)-1H-benzimidazole-5-carboxamide;
683 2-(3,5-Dichloro-pyridin-4-ylamino)-6-methoxy-N-(2,2,3,3,4,4,5,5,5-nonafluoro-penthyl)-1H-benzimidazole-5-carboxamide;
686 2-(3,5-Dichloro-pyridin-4-ylamino)-N-((3-trifluoromethyl-pyridin-2-yl)-methyl)-6-(2-methoxy-ethoxy)-1H-benzimidazole-5-carboxamide;
688 2-(3,5-Dichloro-pyridin-4-ylamino)-N-((3-cyclobutyl-pyridin-2-yl)-methyl)-6-methoxy-1H-benzimidazole-5-carboxamide;
689 2-(3,5-Dichloropyridin-4-ylamino)-N-((2-trifluoromethyl-phen-1-yl)-methyl)-6-ethoxy-1H-benzimidazole-5-carboxamide;
690 2-(3,5-Dichloropyridin-4-ylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-6-ethoxy-1H-benzimidazole-5-carboxamide;
691 2-(3,5-Dichloropyridin-4-ylamino)-N-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-6-ethoxy-1H-benzimidazole-5-carboxamide;
693 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-chloro-pyridin-2-yl)-methyl)-6-ethoxy-1H-benzimidazole-5-carboxamide;
700 2-(3,5-Dichloro-pyridin-2-yl-amino)-N-(2,2,3,3,4,4,5,5,5-nonafluoro-pentyl)-6-(difluoromethoxy)-1H-benzimidazole-5-carboxamide;
701 2-(3,5-Dichloropyridin-4-ylamino)-N-(trans-4-trifluoromethyl-cyclohex-1-yl)-6-difluoromethoxy-1H-benzimidazole-5-carboxamide;
704 2-(3,5-Dichloropyridin-4-ylamino)-N-(4-bromo-phenyl)-6-ethoxy-1-(2,2,2-trifluoroethoxy)-1H-benzimidazole-6-carboxamide; or
711 2-(3,5-Dichloropyridin-4-ylamino)-N-((3-difluoromethyl-pyridin-2-yl)-methyl)-6-(2,2,2-trifluoro-ethoxy)-1H-benzimidazole-5-carboxamide.

### Claim 4 (depends on 1)

A pharmaceutical formulation comprising a compound according to claim 1, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 5 (depends on 1)

A method for the treatment of a disease or condition selected from: asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, a myofascial disorder, a viral infection, a bacterial infection, a fungal infection, dysmenorrhea, a burn, a surgical or dental procedure, a malignancy, hyperprostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, a neurodegenerative disorder, an autoimmune disease, an allergic disorder, rhinitis, an ulcer, coronary heart disease, sarcoidosis, any other disease with an inflammatory component, osteoporosis, osteoarthritis, Paget's disease, a periodontal disease or a cancer, in a patient comprising administering to said patient a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 2)

A pharmaceutical formulation comprising a compound according to claim 2, or a pharmaceutically-acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

### Claim 7 (depends on 2)

A method for the treatment of a disease or condition selected from: asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, pain, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, a myofascial disorder, a viral infection, a bacterial infection, a fungal infection, dysmenorrhea, a burn, a surgical or dental procedure, a malignancy, hyperprostaglandin E syndrome, classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, a neurodegenerative disorder, an autoimmune disease, an allergic disorder, rhinitis, an ulcer, coronary heart disease, sarcoidosis, any other disease with an inflammatory component, osteoporosis, osteoarthritis, Paget's disease, a periodontal disease or a cancer, in a patient comprising administering to said patient a compound according to claim 2, or a pharmaceutically acceptable salt thereof.