Piperazine PDE4 inhibitors and uses thereof

1. A compound of formula I:

wherein:

R 1 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl;

n is 1;

m is 1;

W is O, S, or two hydrogens;

X is N—Y—R 4 ;

Y is a direct bond, —CH 2 —, —C(═O)—, —C(═S)—, —O—, —C(═O)O—, —OC(═O), —C(═O)NR a , —S—, —S(═O)—, —S(═O) 2 —, or —S(═O) 2 NR a —;

R 4 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, hydroxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, carboxy, aryl, aryl(C 1 -C 6 )alkyl, het, NR d R e , —C(═O)NR d R e , NR d R e (C 1 -C 6 )alkyl, or het(C 1 -C 6 )alkyl;

R a is H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl;

Z is a phenyl ring substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; or Z is a phenyl ring that is fused to a saturated, partially unsaturated, or aromatic, mono- or bicyclic ring system comprising from about 3 to about 8 atoms selected from carbon, oxygen, and NR b , wherein the mono- or bicyclic ring system of Z is optionally substituted with one or more R c , and wherein the phenyl ring that is fused to the mono- or bicyclic ring system is optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy;

R b is absent, H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl;

R c is (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl;

each R d and R e is independently H, hydroxy, (C 1 -C 6 )alkyl, amino, amino(C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy, (C 2 -C 6 )alkenyloxy, (C 2 -C 6 )alkynyloxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, NR f R g , or aryl(C 1 -C 6 )alkoxy; and each R f and R g is independently H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, or aryl(C 1 -C 6 )alkoxy; or R f and R g together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino ring;

wherein any aryl or het of R 1 or R 4 is optionally substituted with one or more substitutents independently selected from (C 1 -C 6 )alkyl, phenyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyloxy, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, cyano, nitro, halo, carboxy or NR d R e ;

and wherein the ring containing X is optionally substituted on carbon with one or more halo, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy;

and when R 1 is H or C 1 alkyl, —Y—R 4 is not aryl(C 1 -C 6 ) alkyl or hydroxy(C 1 -C 6 )alkyl;

and when R 1 is H and —Y—R 4 is H, Z is not a phenyl ring substituted with only one halo(C 1 -C 6 )alkyl or only one halo(C 1 -C 6 )alkoxy substituent;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 wherein R 1 is (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkanoyloxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkoxy, aryl(C 1 -C 6 )alkanoyl, het, het(C 1 -C 6 )alkyl, het(C 1 -C 6 )alkoxy, or het(C 1 -C 6 )alkanoyl.

3. The compound of claim 1 wherein R 1 is H, (C 1 -C 6 )alkyl, aryl, aryl(C 1 -C 6 )alkyl, or het.

4. The compound of claim 1 wherein R 1 is H, benzyl, indolyl, phenyl, 2-methylpropyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, α-phenylbenzyl, phenethyl, 1-naphthylmethyl, 2-naphthylmethyl, 4-phenylbenzyl, 4-ethoxybenzyl, isopropyl, cyclohexylmethyl, 2-methoxyphenyl, 3-methoxyphenyl, or 4-methoxyphenyl.

5. The compound of claim 1 wherein Y is a direct bond, —CH 2 —, —C(═O)—, or —S(═O) 2 —.

6. The compound of claim 1 wherein R 4 is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, hydroxy(C 2 -C 6 )alkyl, (C 1 -C 6 )alkoxycarbonyl, carboxy, aryl, aryl(C 1 -C 6 )alkyl, het, NR d R e , —C(═O)NR d R e , NR d R e (C 1 -C 6 )alkyl, or het(C 1 -C 6 )alkyl.

7. The compound of claim 1 wherein Y—R 4 is H, tert-butoxycarbonyl, formylmethyl, pyridylmethyl, methyl, ethylaminocarbonyl, ethylsulfonyl, benzylsulfonyl, benzyl, acetyl, methoxycarbonylmethyl, methylsulfonyl, ethyl, carboxymethyl, propyl, 2-hydroxyethyl, methoxyaminocarbonylmethyl, benzyloxyaminocarbonylmethyl, prop-2-eneyloxyaminocarbonylmethyl, hydroxyaminocarbonylmethyl, hydroxyacetyl, 2-methylhydrazocarbonylmethyl, hydrazocarbonylmethyl, 2,2-dimethylhydrazo-carbonylmethyl, or ethoxycarbonyl.

8. The compound of claim 1 wherein Z is a phenyl ring substituted with one or more substituents independently selected from (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkoxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy.

9. The compound of claim 1 wherein Z is a phenyl ring that is fused to a saturated, partially unsaturated, or aromatic, mono- or bicyclic ring system comprising from about 3 to about 8 atoms selected from carbon, oxygen, and NRb, wherein the mono- or bicyclic ring system of Z is optionally substituted with one or more Rc, and wherein the phenyl ring that is fused is fused to the mono- or bicyclic ring system is optionally substituted with one or more substituents independently selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy.

10. The compound of claim 1 wherein Z has the following formula:

wherein R 2 is (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl; and R 3 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl.

11. The compound of claim 10 wherein R 2 is methyl and R 3 is cyclopentyl.

12. The compound of claim 1 wherein Z is selected from a structure of formula III, IV, and V:

that is optionally substituted with one or more substituents selected from (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; wherein p is 1, 2, 3, 4, 5, or 6.

13. The compound of claim 1 wherein Z is selected from a structure of formula VI, VII, and VIII:

wherein: R j , R k , R m , R n , and R p are each independently selected from H, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 2 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyloxy, and (C 3 -C 8 )cycloalkyl(C 1 -C 6 )alkoxy; and p is 1, 2, 3, 4, 5, or 6.

14. The compound of claim 13 wherein R j , and R k are each independently selected from H and methyl; R m is methoxy; R n is cyclopentyl; R p is ethyl; and p is 3.

15. The compound of claim 1 which is:

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methyl-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methyl-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methyl-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(2-methoxy-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(3-methoxy-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-methoxy-benzyl)-piperazine;

(S)-1-(3-Cyclopentyloxy-4-methoxy-phenyl)-3-(4-ethoxy-benzyl)-piperazine;

(S)-3-Biphenyl-4-ylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

(S)-3-Benzhydryl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

(S)-3-Cyclohexylmethyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine;

3-[(S)-4-(3-Cyclopentyloxy-4-methoxy-phenyl)-piperazin-2-ylmethyl]-1H-indole;

4-[(S)-3-benzyl-1-piperzinyl]-7-methoxy-spiro[benzofuran-2(3H),1′-cyclopentane];

6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-methyl-1H-indazole;

1-Cyclopentyl-3-ethyl-6-piperazin-1-yl-1H-indazole;

6-((S)-3-Benzyl-piperazin-1-yl)-1-cyclopentyl-3-ethyl-1H-indazole;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-2-ylmethyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-3-ylmethyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-pyridin-4-ylmethyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(3H-imidazol-4-ylmethyl)-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-(1H-imidazol-2-ylmethyl)-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-methanesulfonyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-ethanesulfonyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-1-benzylsulfonyl-piperazine;

(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine-1-carboxylic acid ethylamide;

1-[(S)-2-Benzyl-4- (3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone;

2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone, hydrochloride salt;

1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-methylamino-ethanone, hydrochloride salt;

4-[(1((S)-3-benzyl-4-piperazin-1-yl)-2-hydroxy-ethanone)]-7-methoxy-spiro[benzofuran-2(3H), 1′-cyclopentane];

1-[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-2-hydroxy-ethanone;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol;

4-[(1((S)-3-benzyl-4-piperazin-1-yl)-acetic acid)]-7-methoxy-spiro[benzofuran-2(3H), 1′-cyclopentane];

[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-acetic acid;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid hydrazide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′-methyl-hydrazide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′,N′-dimethyl-hydrazide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methoxy-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-ethoxy-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-isobutoxy-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-phenoxy-acetamide;

N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide; or

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide.

16. The compound of claim 1 which is:

1-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-ethanone;

2-Amino-1-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanone, hydrochloride salt;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-ethanol;

4-[(1((S)-3-benzyl-4-piperazin-1-yl)-acetic acid)]-7-methoxy-spiro[benzofuran-2(3H), 1′-cyclopentane];

[(S)-2-Benzyl-4-(1-cyclopentyl-3-ethyl-1H-indazol-6-yl)-piperazin-1-yl]-acetic acid;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-methyl-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-hydroxy-acetamide;

N-Allyloxy-2-[(S)-2-benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetamide;

2-[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-N-benzyloxy-acetamide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid hydrazide;

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′-methyl-hydrazide; or

[(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid N′,N′-dimethyl-hydrazide;

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound of claim 1 , in combination with a pharmaceutically acceptable diluent or carrier.