Uracil derivative and use thereof for medical purposes

• US 9,040,516 B2
• Filed: 07/31/2012
• Issued: 05/26/2015
• Est. Priority Date: 08/01/2011
• Status: Expired due to Fees

• Current Assignee: Sumitomo Dainippon Pharma Company Limited (Sumitomo Chemical Company Limited)
• Original Assignee: Sumitomo Dainippon Pharma Company Limited (Sumitomo Chemical Company Limited)
• Inventors: Kubota, Katsumi, Takanashi, Yosuke, Nakamura, Tomoaki, Shiro, Tomoya, Tobe, Masanori, Sone, Toshihiko
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US14/236,571
• Publication Number:
  US 20140179670A1
• Time in Patent Office: 1,029 Days
• Field of Search: 514/269, 544/316
• US Class Current: 514/210.18
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07F 7/1804 : Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896

Abstract

The present invention provides: an uracil derivative represented by general formula (I) or a physiologically acceptable salt thereof (in the formula, R¹ represents a hydrogen atom, a C_1-10 alkyl group, a C_2-6 alkene group or a 3- to 6-membered saturated or 4- to 6-membered unsaturated aliphatic ring group which may contain 1 to 2 hetero atoms independently selected from the group consisting of N, O and S; R² represents a hydrogen atom, a halogen atom, a cyano group, —NR^cR^d, —N═CHN(CH₃)₂, or an C_1-3 alkyl group; Ar¹ and Ar² independently represent a 5- to 6-membered aromatic ring group which may contain 1 to 3 hetero atoms independently selected from the group consisting of N, O and S; and L represents a 6-membered aromatic ring group which may contain 1 to 4 nitrogen atoms, a pyrazole group, a triazole group, or an imidazole group); and a therapeutic agent or prophylactic agent for various inflammatory diseases associated with elastase, comprises the compound or the like as an active ingredient.

Claims

1. A compound represented by formula (I) or physiologically acceptable salts thereof:

2. The compound according to claim 1 or physiologically acceptable salts thereof, wherein

Z¹ and Z² represent independently of each other a cyano group, a halogen atom, a —

C(═

O)NR^cR^d group, a —

C(═

O)OR^b2 group, a —

CHO group, a nitro group, a —

NR^aC(═

O)R^b group, a hydrogen atom, a —

S(═

O)_mNR^c2R^d2 group, a —

S(═

O)_mNR^aC(O)R^b3 group, a —

S(═

O)_mNR^aC(═

O)OR^b4 group, a —

S(═

O)_mNR^aC(═

O)NR^aR^b3 group, a —

S(═

O)_mR^g2 group, a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S wherein said saturated aliphatic ring group is optionally substituted with halogen, C_1-6 alkyl, —

C(O)OR^a or —

C(═

O)R^a or a C_1-6 alkyl group wherein said alkyl group is optionally substituted with halogen, —

C(═

O)NR^cR^d, —

NR^aS(═

O)_mR^h, —

C(═

O)NR^cR^d or —

C(═

O)OR^a.

3. The compound according to claim 1 or 2 or physiologically acceptable salts thereof wherein

Ar¹ represents a benzene ring or a pyridine ring wherein said benzene ring and said pyridine ring are independently of each other substituted at one to three substitutable positions with C_1-6 alkyl group optionally substituted with hydroxy or halogen, C_1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, phenyl group, —

C(═

O)NR^cR^d group, —

C(═

O)OR^a group, —

C(═

O)R^a group, —

S(═

O)_nR^h group or —

NR^cR^d group, and

Ar² represent a benzene ring or a pyridine ring wherein said benzene ring and said pyridine ring are substituted independently of each other at one to three substitutable positions with C_1-6 alkyl group optionally substituted with hydroxy or halogen, C_1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, nitro group, —

C(═

O)NR^cR^d group, —

C(═

O)OR^a group, —

C(═

O)R^a group, —

S(═

O)_nR^h group or —

NR^cR^d group.

4. The compound according to claim 1 or physiologically acceptable salts thereof wherein

Ar¹ represents the following formula of Ar¹-1:

5. The compound according to claim 1 or physiologically acceptable salts thereof wherein R² represents a —

NR^cR^d group, a —

N═

CHN(CH₃)₂ group or a C_1-3 alkyl group wherein said alkyl group is optionally substituted with hydroxy, halogen, —

NR^cR^d, —

OR^a or —

OC(═

O)R^a.

6. The compound according to claim 1 or physiologically acceptable salts thereof, wherein

R^a represents a hydrogen atom or a C_1-6 alkyl group optionally substituted with hydroxy or halogen,

R^b represents a C_1-6 alkyl group optionally substituted with hydroxy or halogen,

R^b2 represents a hydrogen atom, a C_1-6 alkyl group wherein said alkyl group is optionally substituted with hydroxy, —

NR^aR^b or fluorine or a C_3-6 cycloalkyl group wherein said cycloalkyl group is optionally substituted with hydroxy or fluorine,

R^b3 represents a hydrogen atom, a phenyl group wherein said phenyl group is optionally substituted with fluorine or chlorine, a C_1-6 alkyl group wherein said alkyl group is optionally substituted with hydroxy or fluorine or a C_3-6 cycloalkyl group wherein said cycloalkyl group is optionally substituted with hydroxy or fluorine,

R^b4 represents a hydrogen atom, a phenyl group wherein said phenyl group is optionally substituted with fluorine or chlorine, a C_1-6 alkyl group wherein said alkyl group is optionally substituted with hydroxy or fluorine, a C_3-6 cycloalkyl group wherein said cycloalkyl group is optionally substituted with hydroxy or fluorine or an 2-isopropyl-5-methylcyclohexyl,

R^c and R^d represent independently of each other a hydrogen atom or a C_1-3 alkyl group wherein said alkyl group is optionally substituted with C_1-3 alkoxy, cyano, hydroxy or fluorine, or alternatively may combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group wherein said aliphatic ring group is optionally substituted at substitutable positions with C_1-6 alkyl group wherein said alkyl group is optionally substituted with hydroxy, —

NR^aR^b, —

NR^aC(═

O)OR^h or —

NR^aC(═

O)R^h, C_1-3 alkoxy group, —

NR^aR^b group, —

NR^aC(═

O)OR^a group, —

NR^aC(═

O)R^a group, —

C(═

O)OR^a group, hydroxy group, fluorine atom or oxo group,

R^c2 an R^d2 represent independently of each other a hydrogen atom or a C_1-3 alkyl group wherein said alkyl group is optionally substituted with phenyl group optionally substituted with methoxy, —

NR^aR^b group, —

NR^a(C═

O)OR^h group, —

NR^aC(═

O)R^h group, C_1-3 alkoxy group, cyano group, hydroxy group or fluorine atom, or alternatively combine each other together with N to which they are attached and optionally together with further one to two heteroatoms independently selected from the group consisting of N, O and S to represent a four to six-membered saturated aliphatic ring group wherein said aliphatic ring group is optionally substituted at substitutable positions with C_1-6 alkyl, C_1-3 alkoxy, —

NR^aR^b, —

NR^aC(═

O)OR^h, —

NR^aC(═

O)R^h, —

C(═

O)OR^a, hydroxy, fluorine or oxo,

R^e represents a C_1-6 alkyl group wherein said alkyl group is optionally substituted with hydroxy or fluorine, an -A group, an C_1-6 alkylcarbonyl group wherein the alkyl moiety of said alkylcarbonyl group is optionally substituted with hydroxy or fluorine or a —

S(═

O)₂R^b group,

R^f represents a hydroxy group, an -A group or an —

NR^aRⁱ group,

R^g represents a hydroxy group, a C_1-3 alkyl group wherein said alkyl group is optionally substituted with hydroxy, fluorine or —

NR^cR^d, a chlorine atom, an -A group or a —

NR^aRⁱ group,

R^g2 represents a hydroxy group, a C_1-3 alkyl group wherein said alkyl group is optionally substituted with hydroxy or fluorine, a chlorine atom or an -A group,

R^g3 represents a C_1-6 alkyl group wherein aid alkyl group is optionally substituted with hydroxy, fluorine or —

NR^cR^d,

R^h represents a C_1-3 alkyl group optionally substituted with hydroxy or fluorine,

Rⁱ represents a C_1-3 alkyl group wherein said alkyl group is optionally substituted with hydroxy, C_1-3 alkoxy or fluorine or an -A group,

A represents

an aromatic ring group selected from the group consisting of phenyl, pyridyl and tetrazolyl wherein said aromatic ring group is optionally substituted at substitutable positions with hydroxy or fluorine or

an aliphatic ring group selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl wherein said aliphatic ring group is optionally substituted at substitutable positions with C_1-3 alkyl, C_1-3 alkoxy, hydroxy, fluorine, —

NR^cR^d or oxo, and

m represents an integer of 1 or 2.

7. The compound according to claim 1 or physiologically acceptable salts thereof wherein

R¹ represents a C_1-10 alkyl group wherein said alkyl group is optionally substituted at substitutable positions with one to three substituents selected from the group consisting of

Substituent List 8:

(1) hydroxy group,

(2) halogen atom,

(3) cyano group,

(7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S wherein said aliphatic ring group is optionally substituted at substitutable positions with

C_1-3 alkyl group optionally substituted with hydroxy or halogen,

C_1-3 alkoxy group optionally substituted with hydroxy or halogen,

hydroxy group,

halogen atom,

cyano group,

—

NR^aC(═

O)R^b,

—

NR^aS(═

O)_mR^b,

—

C(═

O)OR^b,

—

C(═

O)NR^cR^d,

—

C(═

O)R^b,

—

NR^cR^d or

oxo group;

(8) —

NR^aR^e group,

(10) —

C(═

O)R^f group,

(11) —

S(═

O)_mR^g group, and

(12) thiol group,

or

a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S wherein said aliphatic ring group is optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of

Substituent List 9;

(1) hydroxy group,

(2) halogen atom,

(3) cyano group,

(4) C_1-6 alkyl group wherein said alkyl group is optionally substituted at substitutable positions with

hydroxy group,

halogen atom,

cyano group,

five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S wherein said aromatic ring group is optionally substituted at substitutable positions with C_1-3 alkyl group optionally substituted with hydroxy or halogen, C_1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —

NR^aC(═

O)R^b group, —

NR^aS(═

O)_mR^b group, —

C(═

O)OR^b group, —

C(═

O)NR^cR^d group, —

S(═

O)_mNR^cR^d group, —

S(O)_mR^b group or —

NR^cR^d group or

three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S wherein said aliphatic ring group is optionally substituted at substitutable positions with C_1-3 alkyl group optionally substituted with hydroxy or halogen, C_1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —

NR^aC(═

O)R^b group, —

NR^aS(═

O)_mR^b group, —

C(═

O)OR^b group, —

C(═

O)NR^cR^d group, —

NR^cR^d group or oxo group,

(5) C_1-6 alkoxy group wherein said alkoxy group is optionally substituted at substitutable positions with

hydroxy group,

halogen atom,

cyano group,

five to six-membered aromatic ring group optionally containing one to four heteroatoms independently selected from the group consisting of N, O and S wherein said aromatic ring group is optionally substituted at substitutable positions with C_1-3 alkyl group optionally substituted with hydroxy or halogen, C_1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —

NR^aC(═

O)R^b group, —

NR^aS(═

O)_mR^b group, —

C(═

O)OR^b group, —

C(═

O)NR^cR^d group, —

S(═

O)_mNR^cR^d group, —

S(═

O)_mR^b group or a —

NR^cR^d group or

three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S wherein said aliphatic ring group is optionally substituted at substitutable positions with C_1-3 alkyl group optionally substituted with hydroxy or halogen, C_1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy group, halogen atom, cyano group, —

NR^aC(═

O)R^b group, —

NR^aS(═

O)_mR^b group, —

C(═

O)OR^b group, —

C(═

O)NR^cR^d group, —

NR^cR^d group or oxo group,

(11) —

C(═

O)R^f group,

(12) —

S(═

O)_mR^g group, and

(14) oxo group.

8. The compound according to claim 1 or physiologically acceptable salts thereof wherein

R¹ represents

a C_1-10 alkyl group wherein said alkyl group is optionally substituted at substitutable positions with one to three substituents selected from the group consisting of

Substituent List 10:

(1) hydroxy group,

(2) halogen atom,

(7) three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N, O and S wherein said aliphatic ring group is optionally substituted at substitutable positions with C_1-3 alkyl group optionally substituted with hydroxy or halogen, C_1-3 alkoxy group optionally substituted with hydroxy or halogen, hydroxy, halogen, —

C(═

O)OR^b, —

C(═

O)NR^cR^d, —

C(═

O)R^b or oxo group,

(8) —

NR^aR^e group, and

(11) —

S(═

O)₂R^g group

or

a three to six-membered saturated aliphatic ring group optionally containing one to two heteroatoms independently selected from the group consisting of N and O wherein said aliphatic ring group is optionally substituted at substitutable positions with one or multiple substituents selected from the group consisting of

Substituent List 11;

(1) hydroxy group,

(2) halogen atom,

(4) C_1-6 alkyl group wherein said alkyl group is optionally substituted at substitutable positions with hydroxy or halogen,

(9) —

NR^aR^e group,

(11) —

C(═

O)R^f group and

(14) oxo group.

9. The compound according to claim 1 or physiologically acceptable salts thereof wherein L represents a Pyr-1 group.

10. The compound according to claim 1 or physiologically acceptable salts thereof wherein

the formula (I) represents the following formula (I′

″

);

11. The compound according to claim 10 or physiologically acceptable salts thereof wherein

Z¹ represents a —

C(═

O)NR^cR^d group, a —

C(═

O)OR^b2 group, a —

S(═

O)₂NR^c2R^d2 group, a —

S(═

O)₂NR^a2C(═

O)R^b3 group, a —

S(═

O)₂NR^aC(═

O)OR^b4 group, a —

S(═

O)—

NR^aC(═

O)NR^aR^b3 group, a S(═

O)₂R^g group, an iodine atom, a bromine atom or a chlorine atom, and

R² represents a C_1-3 alkyl group optionally substituted with hydroxy.

12. The compound according to claim 1 selected from the following Group or physiologically acceptable salts thereof,

Group:

4-[5-[3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,

4-[5-[6-Methyl-2,4-dioxo-3-propyl-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,

4-(5-(3-Ethyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

4-[5-[1-(3-Chlorophenyl)-3,6-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile,

4-(5-(3,6-Dimethyl-2,4-dioxo-1-m-tolyl-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

4-(5-(6-Ethyl-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

(R)-4-(5-(3-(1-Hydroxypropan-2-yl)-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

4-(4-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazol-3-yl)benzonitrile,

(S)-4-(5-(2,4-Dioxo-3-(5-oxopyrrolidin-3-yl)1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

1-(4-Cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxamide,

4-(Dimethylamino)butyl 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxylate,

(±

)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonic acid,

(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,

(−

)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonaic acid,

(±

)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphienyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,

(−

)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,

(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,

(+)-1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide.0.5 IPA solvates,

(±

)-1-(4-Cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,

(+)-1-(4-Cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide,

N-(1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyridin-5-yl)-1H-pyrazole-4-ylsulfonyl)pivalamine,

Butyl 1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonylcarbamate,

N-(1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-ylsulfonyl)benzamide,

1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(ethylcarbonyl)-1H-pyrazole-4-sulfonamide,

(±

)-4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,

(+)-4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,

(±

)-4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile,

4-(5-(3-Ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)benzonitrile,

(R)-4-(5-(6-Methyl-2,4-dioxo-3-(pyrolidin-3-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

4-(5-(3,6-Dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4-fluoro-1H-pyrazol-1-yl)benzonitrile,

4-(4-Chloro-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carbonitrile,

(R)-4-(5-(6-Methyl-3-(methanesulfonyl)propan-2-yl)-2,4-dioxo-3-(1-oxopropane-2-yl)-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile,

(R)-2-(5-(1-(4-Cyanophenyl)-1H-pyrazol-5-yl)-4-methyl-2,6-dioxo-3-(3-trifluoromethylphenyl)-2,3-dihydropyrimidin-1(6H)-yl)propane-1-sulfonamide and

5-(4-Cyanophenyl)-4-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-4H-1,2,4-triazole-3-carboxamide.

13. A method of treating inflammatory diseases or cancers, comprising the step of:

administering the compound according to claim 1 or physiologically acceptable salts thereof to a patient in need thereof.

14. A pharmaceutical composition for use in treatment or prophylaxis of inflammatory diseases or cancers comprising the compound according to claim 1 or physiologically acceptable salts thereof as active ingredient.

15. The compound according to claim 1, wherein the compound is 4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile or physiologically acceptable salts thereof.

16. The compound according to claim 1, wherein the compound is 1-(4-cyanophenyl)-5-(3-isopropyl-6-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-carboxamide or physiologically acceptable salts thereof.

17. The compound according to claim 1, wherein the compound is (+)-1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide or physiologically acceptable salts thereof.

18. The compound according to claim 1, wherein the compound is (±

)-1-(4-cyanophenyl)-5-(3-ethyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide or physiologically acceptable salts thereof.

19. The compound according to claim 1, wherein the compound is (+)-4-(5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile or physiologically acceptable salts thereof.

20. The compound according to claim 1, wherein the compound is (±

)-4-(5-(3-Isopropyl-6-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl-4-(methylsulfonyl)-1H-pyrazol-1-yl)benzonitrile or physiologically acceptable salt thereof.