IP Library › Granted Patent US 8,765,949

Granted Patent B2

US 8,765,949 · App. 12/969,745 · Granted Jul 1, 2014

CCR2 receptor antagonists and uses thereof

Inventors: Heiner Ebel (Biberach, DE); Sara Frattini (Castelleone, IT); Kai Gerlach (Mittelbiberach, DE); Riccardo Giovannini (Verona, IT); Christoph Hoenke (Ingelheim, DE); Rocco Mazzaferro (San Giuliano Milanese, IT); Marco Santagostino (Mittelbiberach, DE); Stefan Scheuerer (Warthausen, CZ); Christofer Tautermann (Biberach, DE); Thomas Trieselmann (Warthausen, DE)

Assignee: Boehringer Ingelheim International GmbH

C07D405/14 C07D491/107

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Quick Facts

Patent No.: US 8,765,949
App. No.: 12/969,745
Granted: Jul 1, 2014
Kind: B2

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Abstract

The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.

Claims (224)

1. A compound of formula (I),

wherein:

R 1 is selected from —H, -halogen, —CN, —O—C 1 -C 4 -alkyl, —C 1 -C 4 -alkyl, —CH═CH 2 , —C≡CH, —CF 3 , —OCF 3 , —OCF 2 H, and —OCFH 2 ;

R 7 is a ring selected from —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -heterocyclyl, —C 5 -C 10 -aryl, and —C 5 -C 10 -heteroaryl,

wherein the ring R 7 is optionally substituted with one or more groups selected from —CF 3 , —O—CF 3 , —S—CF 3 , —CN, —C 1 -C 6 -alkyl, —C(CH 3 ) 2 —CN, and -halogen,

or wherein the ring R 7 is optionally substituted with one or more groups selected from —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —C 5 -C 10 -aryl, —C 5 -C 10 -heteroaryl, —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -heterocyclyl, —C 2 -C 6 -alkenyl, and —C 2 -C 6 -alkynyl,

optionally being substituted by one or more groups selected from —OH, —NH 2 , —C 1 -C 3 -alkyl, —O—C 1 -C 6 -alkyl, —CN, —CF 3 , —OCF 3 , halogen, -methyl, and ═O;

R 2 is selected from —H, -halogen, —CN, —O—C 2 -C 4 -alkyl, —C 1 -C 4 -alkyl, —CH═CH 2 , —C≡CH, —CF 3 , —OCF 3 , —OCF 2 H, and —OCFH 2 ;

R 3 is selected from —H, -methyl, -ethyl, -propyl, -1-propyl, -cyclopropyl, —OCH 3 , —CF 3 , and —CN;

n is 2;

G and E are independently selected from C—H or N, wherein at least one of E or G is N;

Z is C,

and R 4 and R 5 are independently selected from —H, —C 1 -C 6 -alkyl, —NH 2 , —C 3 -C 8 -cycloalkyl, —C 3 -C 8 -heterocyclyl, C 5 -C 10 -aryl, —C 5 -C 10 -heteroaryl, and —C(O)—N(R 8 ,R 8′ ), with R 8′ and R 8′ independently being selected from —H, and —C 1 -C 6 -alkyl;

and R 4 and R 5 if different from —H are optionally independently substituted with one or more groups selected from -halogen, —OH, —CF 3 , —CN, —C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkyl, —O—C 3 -C 8 -cycloalkyl, —O—C 3 -C 8 -heterocyclyl, —O—C 5 -C 10 -aryl, —O—C 5 -C 10 -heteroaryl, —C 0 -C 6 -alkylene-CN, —C 0 -C 4 -alkylene-O—C 1 -C 4 -alkyl, —C 0 -C 4 -alkylene-O—C 3 -C 8 -cycloalkyl, —C 0 -C 4 -alkylene-O—C 3 -C 8 -heterocyclyl, —C 0 -C 4 -alkylene-O—C 5 -C 10 -aryl, —C 0 -C 4 -alkylene-O—C 5 -C 10 -heteroaryl, —C 0 -C 4 -alkylene-Q-C 0 -C 4 -alkyl-N(R 9 ,R 9′ ), —C 0 -C 4 -alkylene-N(R 10 )-Q-C 1 -C 4 -alkyl, —C 0 -C 4 -alkylene-N(R 10 )-Q-C 3 -C 8 -cycloalkyl, —C 0 -C 4 -alkylene-N(R 10 )-Q-C 3 -C 8 -heterocyclyl, —C 0 -C 4 -alkylene-N(R 10 )-Q-C 5 -C 10 -aryl, —C 0 -C 4 -alkylene-N(R 10 )-Q-C 5 -C 10 -heteroaryl, —C 0 -C 4 -alkylene-Q-N(R 11 ,R 11′ ), —C 0 -C 4 -alkylene-N(R 12 )-Q-N(R 13 ,R 13′ ), —C 0 -C 4 -alkylene-R 14 , —C 0 -C 4 -alkylene(R 20 ,R 20′ ), —C 0 -C 4 -alkylene-Q-C 1 -C 6 -alkyl, —C 0 -C 4 -alkylene-Q-C 3 -C 8 -cycloalkyl, —C 0 -C 4 -alkylene-Q-C 3 -C 8 -heterocyclyl, —C 0 -C 4 -alkylene-Q-C 5 -C 10 -aryl, —C 0 -C 4 -alkylene-Q-C 5 -C 10 -heteroaryl, —C 0 -C 4 -alkylene-O-Q-N(R 15 ,R 15′ ), and —C 0 -C 4 -alkylene-N(R 16 )-Q-O—(R 17 );

wherein Q is selected from —C(O)—, and —SO 2 —;

R 10 , R 12 , R 16 , are independently selected from —H, —C 1 -C 6 -alkyl, and —C 3 -C 6 -cycloalkyl,

wherein R 9 , R 9′ , R 11 , R 11′ , R 13 , R 13′ , R 15 , R 15′ , are independently selected from —H, —C 1 -C 6 -alkyl, and —C 3 -C 6 -cycloalkyl, or

R 9 and R 9′ , R 11 and R 11′ , R 13 and R 13′ , R 15 and R 15′ together form a —C 2 -C 6 -alkylene group;

R 14 and R 17 are independently selected from —H, —C 1 -C 6 -alkyl, -C 5 -C 10 -aryl, -C 5 -C 10 -heteroaryl, —C 3 -C 8 -cycloalkyl, and —C 3 -C 8 -heterocyclyl, wherein said —C 3 -C 8 -heterocyclyl optionally comprises nitrogen and/or —SO 2 — in the ring;

wherein R 14 and R 17 are optionally substituted with one or more groups selected from —OH, —OCH 3 , —CF 3 , —COOH, —OCF 3 , —CN, -halogen, —C 1 -C 4 -alkyl, ═O, and —SO 2 —C 1 -C 4 -alkyl; and

R 20 and R 20′ together form a spiro-C 3 -C 8 -carbocycle or spiro-C 3 -C 8 -heterocycle comprising one or more group selected from O in the ring, and wherein said spirocycle is optionally further bi-valently substituted by an annellated ring forming group selected from —C 1 -C 6 -alkylene, —C 2 -C 6 -alkenylene, and —C 4 -C 6 -alkynylene and wherein said spirocycle is optionally further substituted with one or more groups selected from —OH, —OCH 3 , —CF 3 , —COOH, —OCF 3 , —CN, -halogen;

or Z is C,

and R 4 denotes —H and R 5 is a group of the structure -L 1 -R 18 ,

wherein L 1 is selected from —NH—, —N(C 1 -C 4 -alkyl)-, and a bond,

R 18 is selected from —C 5 -C 10 -aryl, -C 5 -C 10 -heteroaryl, —C 3 -C 8 -cycloalkyl, and —C 3 -C 8 -heterocyclyl, wherein

R 18 is optionally substituted by one or more groups selected from halogen, —CF 3 , —OCF 3 , —CN, —OH, —O—C 1 -C 4 -alkyl, —C 1 -C 6 -alkyl, —NH—C(O)—C 1 -C 6 -alkyl, —N(C 1 -C 4 -alkyl)-C(O)—C 1 -C 6 -alkyl, —C(O)—C 1 -C 6 -alkyl, —S(O) 2 —C 1 -C 6 -alkyl, —NH—S(O) 2 —C 1 -C 6 -alkyl, —N(C 1 -C 4 -alkyl)-S(O) 2 —C 1 -C 6 -alkyl, and —C(O)—O—C 1 -C 6 -alkyl,

and R 4 , R 5 and R 18 are optionally further substituted by spiro-C 3 -C 8 -cycloalkyl or spiro-C 3 -C 8 -heterocyclyl such that together with R 4 , R 5 and/or R 18 a spirocycle is formed, wherein said spiro-C 3 -C 8 -heterocyclyl optionally comprises one or more groups selected from nitrogen, —C(O)—, —SO 2 —, and —N(SO 2 —C 1 -C 4 -alkyl)- in the ring;

and;

R 6 is selected from —H, —C 1 -C 4 -alkyl, —OH, —O—C 1 -C 4 -alkyl, -halogen, —CN, —CF 3 , and —OCF 3 ; or

an acid addition salt with a pharmacologically acceptable acid.

2. The compound of claim 1 , wherein:

R 4 and R 5 are independently selected from —H, -i-propyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and —C(O)—N(R 8 ,R 8′ ), wherein R 8 and R 8′ are independently selected from —H and —C 1 -C 6 -alkyl, and wherein R 4 and R 5 if different from —H are optionally independently substituted with one or more groups selected from -fluoro, -methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl, -hydroxy, —CF 3 , —OCF 3 , —CN, —O—CH 3 , —O—C 2 H 5 , —O—C 3 H 7 , —CH 2 —CN, —CH 2 —O—CH 3 , —(CH 2 ) 2 —O—CH 3 , —C(O)—CH 3 , —C(O)—C 2 H 5 , —C(O)—C 3 H 7 , —COOH, —C(O)—NH 2 , —C(O)—NH—CH 3 , —C(O)—N(CH 3 ) 2 , —NH—C(O)—CH 3 , —N(CH 3 )C(O)—CH 3 , —NH—C(O)—C 2 H 5 , —N(CH 3 )—C(O)—C 2 H 5 , —NH—C(O)—C 3 H 7 , —N(CH 3 )—C(O)—C 3 H 7 , —NH—SO 2 —CH 3 , —N(CH 3 )—SO 2 —CH 3 , —N(C 2 H 5 )—SO 2 —CH 3 , —N(C 3 H 7 )—SO 2 —CH 3 , —NH—SO 2 —C 2 H 5 , —N(CH 3 )—SO 2 —C 2 H 5 , —N(C 2 H 5 )—SO 2 —C 2 H 5 , —N(C 3 H 7 )—SO 2 —C 2 H 5 , —NH—SO 2 —C 3 H 7 , —N(CH 3 )—SO 2 —C 3 H 7 , —N(C 2 H 5 )—SO 2 —C 3 H 7 , —N(C 3 H 7 )—SO 2 —C 3 H 7 , —NH—SO 2 —C 3 H 5 , —N(CH 3 )—SO 2 —C 3 H 5 , —N(C 2 H 5 )—SO 2 —C 3 H 5 , —N(C 3 H 7 )—SO 2 —C 2 H 5 , —CH 2 —NH—SO 2 —CH 3 , —CH 2 —N(CH 3 )—SO 2 —CH 3 , —CH 2 —NH—SO 2 —C 2 H 5 , —CH 2 —N(CH 3 )—SO 2 —C 2 H 5 , —CH 2 —NH—SO 2 —C 3 H 7 , —CH 2 —N(CH 3 )—SO 2 —C 3 H 7 , —CH 2 —NH—SO 2 —C 3 H 5 , —CH 2 —N(CH 3 )—SO 2 —C 3 H 5 , —NH—C(O)—NH 2 , —N(CH 3 )—C(O)—NH 2 , —NH—C(O)—NH—CH 3 , —N(CH 3 )—C(O)—NH—CH 3 , —NH—C(O)—N(CH 3 ) 2 , —N(CH 3 )—C(O)—N(CH 3 ) 2 , —SO 2 —NH 2 , —SO 2 —NH(CH 3 ), —SO 2 —N(CH 3 ) 2 , —C(O)—NH—C 2 H 5 , —C(O)—N(CH 3 )—C 2 H 5 , —C(O)—N(CH 3 )—C 3 H 7 , —C(O)—N(CH 3 )—C 4 H 9 , —C(O)—NH—CH(CH 3 )—C 2 H 5 , —C(O)—N(CH 3 )—CH(CH 3 )—C 2 H 5 , —CH 2 —C(O)—NH 2 , —CH 2 —C(O)—NH—CH 3 , —CH 2 —C(O)—N(CH 3 ) 2 , —N(CH 3 )—SO 2 —N(CH 3 ) 2 , —(C 6 -aryl)-COOH, -phenyl, -pyridin-4-yl, —CH 2 -3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,

R 4 denotes —H and R 5 is a group of the structure -L 1 -R 18 ,

wherein L 1 is selected from —NH—, —N(CH 3 )—, and —N(C 2 H 5 )—,

and R 18 is selected from -tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl, -octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl, -octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and -tetrahydro-naphthyridinyl, and

R 18 is optionally substituted by one or more groups selected from —F, —CF 3 , —OCF 3 , —CN, —OH, —O—CH 3 , —CH 3 , —NH—C(O)—CH 3 , —N(CH 3 )—C(O)—CH 3 , —C(O)—CH 3 , —S(O) 2 —CH 3 , —NH—S(O) 2 —CH 3 , —N(CH 3 )—S(O) 2 —CH 3 , —N(CH 3 )—S(O) 2 —CH 2 —CH 3 , and —C(O)—O—C 2 H 5 .

3. The compound of claim 1 , wherein R 7 is selected from —C 5 -C 6 -aryl, —C 5 -C 6 -heteroaryl, —C 3 -C 8 -cycloalkyl, and —C 3 -C 8 -heterocyclyl,

wherein the ring R 7 is optionally substituted with one or more groups selected from —CF 3 , —O—CF 3 , —S—CF 3 , —CN, -methyl, —C(CH 3 ) 2 —CN, and -halogen.

4. The compound of claim 1 , wherein R 7 is selected from —C 5 -C 6 -aryl, and —C 5 -C 6 -heteroaryl,

wherein the ring R 7 is optionally substituted with one or more groups selected from —CF 3 , —O—CF 3 , —S—CF 3 , —CN, -methyl, —F, —Cl, —C(CH 3 ) 2 —CN, and —Br.

5. The compound of claim 1 wherein:

R 4 is —H; and

R 5 is a group -L 1 -R 18 ,

wherein L 1 is selected from —NH—, —N(CH 3 )—, —N(C 2 H 5 )—, and a bond,

and R 18 is selected from —C 6 -heterocyclyl comprising 1 or 2 hetero atoms selected from N, and O, and

R 18 is optionally substituted with one or more groups selected from —F, —CF 3 , —OCF 3 , —CN, —OH, —O—CH 3 , —CH 3 , —NH—C(O)—CH 3 , —N(CH 3 )—C(O)—CH 3 , —C(O)—CH 3 , —S(O) 2 —CH 3 , —NH—S(O) 2 —CH 3 , —N(CH 3 )—S(O) 2 —CH 3 , —N(CH 3 )—S(O) 2 —CH 2 —CH 3 , and —C(O)—O—C 2 H 5 ; or

R 4 and R 5 are independently selected from —H and —C 1 -C 6 -alkyl.

6. The compound of claim 1 , wherein R 2 is selected from —H, -methyl, -ethyl, -propyl, -i-propyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH 2 , and —C≡CH.

7. The compound of claim 6 , wherein R 2 is methyl.

8. The compound of claim 6 , wherein R 2 is —H.

9. The compound of claim 1 , wherein R 3 is selected from —H, —CF 3 , —O—CH 3 , and -methyl.

10. The compound of claim 9 , wherein R 3 is H.

11. The compound claim 9 , wherein R 3 is —CF 3 .

12. The compound of claim 1 , wherein R 6 is selected from —H, —CH 3 , —C 2 H 5 , —O—CH 3 , —O—C 2 H 5 , —F, —CF 3 , and —OCF 3 .

13. The compound of claim 12 , wherein R 6 is selected from —H and —O—CH 3 .

14. The compound of claim 1 , wherein R 1 is —H.

15. The compound of claim 1 , wherein G and E are N.

16. A compound selected from the group consisting of

Ex #

STRUCTURE

28a

28b

28c

28d

28e

28f

28g

28h

28i

28j

28k

28l

28m

28n

53a

53b

53c

53d

53e

53f

53g

53h

53i

53j

53k

53l

53m

53n

53o

53p

53q

53r

53s

53t

53u

53v

53w

53x

53y

53z

53aa

53ab

53ac

53ad

53ae

53af

53ag

53ah

53ai

53aj*

53ak*

53al

53am

54a

and the acid addition salts with a pharmacologically acceptable acid.

17. The compound according to claim 1 , wherein the compound is