Pyrazolyl substituted xanthines
View Patent ↗The present invention provides compounds and pharmaceutical compositions that are substituted xanthines of formula I: or pharmaceutically acceptable salts thereof, wherein: Z is selected from the group consisting of oxazoyl, isoxazoyl, thiazolyl, and isothiazoyl; and Z 1 is a 5-14 member substituted or unsubstituted heteroaryl ring; which are selective antagonists of A 2B adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.
1. A compound of formula I:
wherein:
R is hydrogen or is selected from the group consisting of (C 1-5 )alkyl, halo(C 1-8 )alkyl, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 3-5 )alkenyl and (C 3-5 )alkynyl, each substituted or unsubstituted;
one of R 1 and R 2 is selected from the group consisting of cyclopropyl, cyclopropylmethyl, cyclobutyl, hydroxycyclobutyl, trihalomethylcyclobutyl and cyclopentyl;
the other of R 1 and R 2 are each independently is selected from the group consisting of hydrogen, substituted or unsubstituted (C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkenyl(C 1-8 )alkyl, (C 3-8 )alkynyl, (C 3-8 )alkynyl(C 1-8 )alkyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 4-10 )heterocyclyl, (C 4-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryloxy, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl and (C 5-10 )heteroaryl(C 1-8 )alkyl-;
L and L 1 are each independently a linker selected from the group consisting of substituted or unsubstituted —NR°—C(O)—, —NCH 3 —C(O)—, —NR°—S(O)—, —NCH 3 —S(O)—, —NR°—S(O) 2 —, —NCH 3 —S(O) 2 —, —C(O)NR°—, —C(O)NCH 3 —, —NR°C(O)CH 2 —, —NR°C(O)CH 2 CH 2 —, —C(O)NR°CH 2 —, —C(O)NR°CH 2 CH 2 —, —C(O)CH 2 NR°—, —C(O)CH 2 CH 2 NR°—, —CH 2 NR°C(O)—, —CH 2 CH 2 NR°C(O)—, —CH 2 C(O)NR°—, —CH 2 CH 2 C(O)NR°—, —NR°CH 2 C(O)— and —NR°CH 2 CH 2 C(O)—, wherein each R° is independently hydrogen or substituted or unsubstituted (C 1-4 )alkyl, (C 1-4 )alkylC(O)—, (C 6-10 )arylC(O)— and (C 5-10 )heteroarylC(O)—;
Z is selected from the group consisting of oxazoyl, isoxazoyl, thiazolyl, and isothiazoyl;
Z 1 is a 5-14 member substituted or unsubstituted heteroaryl ring;
where m is 0, 1 or 2;
n is 1 or 2; or
a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein:
L and L 1 are each independently unsubstituted or further substituted by a substituent selected from the group consisting of (C 1-4 )alkoxy, (C 1-8 )alkylamino, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 1-4 )alkoxy(C 1-4 )alkyl, halo, hydroxy, cyano, nitro, (C 1-8 )alkyl, (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , (C 1-8 )alkyl)C(O)—, (C 1-8 )alkylCO 2 —, —C(O)N((C 1-8 )alkyl) 2 , —S(O)(C 1-8 )alkyl, —S(O)N((C 1-8 )alkyl) 2 , —S(O) 2 (C 1-8 )alkyl, —S(O) 2 N((C 1-8 )alkyl) 2 , —S(O) 1-2 —NR 4 R 5 , —NR 4 R 5 , (C 4-10 )heterocyclyl(C 1-8 )alkyl-, or (C 4-10 )heterocyclyl wherein the heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 1-8 )alkyl, (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , (C 1-8 )alkyl)C(O)—, (C 1-8 )alkylCO 2 —, —C(O)N((C 1-8 )alkyl) 2 , —S(O)(C 1-8 )alkyl, —S(O)N((C 1-8 )alkyl) 2 , —S(O) 2 (C 1-8 )alkyl, —S(O) 2 N((C 1-8 )alkyl) 2 , —C(O)R b , —COOR b , and —C(O)NR b R c ; wherein R a is hydrogen, or (C 1-6 )alkyl; R b and R c are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkyl-S—, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl, or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or thiomorpholinyl ring; and
wherein R 4 and R 5 each are each independently hydrogen or are selected from the group consisting of (C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 6-18 )polycycloalkyl, (C 6-18 )polycycloalkyl(C 1-8 )alkyl-, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, ((C 1-8 )alkyl) 2 N—(C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, (C 5-10 )heteroaryl(C 1-8 )alkyl-, (C 1-8 )alkyl)C(O)—, (C 1-8 )alkylCO 2 —, —C(O)N((C 1-8 )alkyl) 2 , —S(O)(C 1-8 )alkyl, —S(O)N((C 1-8 )alkyl) 2 , —S(O) 2 (C 1-8 )alkyl or —S(O) 2 N((C 1-8 )alkyl) 2 .
3. The compound of claim 1 , wherein Z 1 is a substituted or unsubstituted heteroaryl ring selected from the group consisting of benzo[b]furan, benzo[b]thiophene, benzimidazole, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, pteridine, purine, carbazole, acridine, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, thiodiazolyl, thiophenyl, pyrrolyl, pyrazolyl, pyrazinyl, tetrazolyl, pyridinyl, pyrimidinyl, indolyl, isoquinolyl and quinolyl.
4. The compound of claim 3 , wherein Z 1 is a substituted or unsubstituted heteroaryl ring selected from the group consisting of imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[1,2a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, pteridine, purine, pyridinyl and pyrimidinyl.
5. The compound of claim 3 , wherein Z 1 is a substituted or unsubstituted heteroaryl ring selected from the group consisting of benzo[b]furan, benzo[b]thiophene, benzimidazole, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiazole, carbazole, acridine, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, thiodiazolyl, pyrrolyl, pyrazolyl, pyrazinyl, tetrazolyl, indolyl, isoquinolyl and quinolyl.
6. The compound of claim 3 wherein Z 1 is substituted by 1, 2 or 3 substituents independently selected from the group consisting of (C 1-8 )alkyl, (C 2-8 )alkenyl, (C 2-8 )alkynyl, —OR 6 , —SR 6 , cyano, nitro, halo, hydroxy, R 6 O(C 1-8 )alkyl, R 7 R 8 N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NC(O)R 6 , —NR 7 R 8 , R 7 R 8 N(C 1-8 )alkyl, —C(O)R 6 , —COOR 6 and —C(O)NR 7 R 8 ;
R 6 is hydrogen, (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl or (C 4-10 )heteroaryl(C 1-8 )alkyl-; wherein the heterocyclyl, heteroaryl or aryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, (C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
R 7 and R 8 are each independently hydrogen, (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl; —COOR b , —C(O)R b or —C(O)NR b R c wherein the heterocyclyl, heteroaryl or aryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7 or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally consisting of 1, 2, 3 or 4 heteroatoms selected from non-peroxide oxy, —S—, sulfinyl, sulfonyl or —NH— in the ring; and,
R a is hydrogen, or (C 1-6 )alkyl; R b and R c are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkyl-S—, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or thiomorpholinyl ring.
7. The compound of claim 3 wherein Z 1 is substituted by 1, 2 or 3 substituents independently selected from the group consisting of amino, carbonyl, cyano, halo, hydroxy, mercapto, (C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkoxy, aryloxy, heteroaryloxy, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 4-10 )heterocyclyl, (C 4-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl and (C 5-10 )heteroaryl(C 1-8 )alkyl-, each substituted or unsubstituted.
8. The compound of claim 3 wherein Z 1 is substituted by 1, 2 or 3 substituents independently selected from the group consisting of (C 1-4 )alkyl, (C 3-4 )alkenyl, (C 3-4 )alkynyl, phenyl, phenyl(C 1-4 )alkyl, (C 3-6 )cycloalkyl and (C 3-6 )cycloalkyl(C 1-4 )alkyl-.
9. The compound of claim 3 wherein Z 1 is substituted by 1, 2 or 3 substituents independently selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, phenyl, phenethyl, benzyl, (methoxyphenyl)ethyl, (C 3-6 )cycloalkyl and (C 3-6 )cycloalkyl(C 1-4 )alkyl-.
10. The compound of claim 3 wherein Z 1 is substituted by 1, 2 or 3 substituents independently selected from the group consisting of —OR 3 , —SR 3 , halo, hydroxy, —S(O) 1-3 —NR 4 R 5 , —NR 4 R 5 , —NC(O)R 6 or (C 4-10 )heterocyclyl wherein the heterocyclyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 1-8 )alkyl, (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ; wherein R a is hydrogen, or (C 1-6 )alkyl; R b and R c are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkyl-S—, (C 6-10 )aryl, (C 6-10 ) aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or thiomorpholinyl ring;
R 3 is (C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, (C 5-10 )heteroaryl(C 1-8 )alkyl-, —C(O)R 6 or —C(O)NR 7 R 8 ;
R 4 and R 5 are independently hydrogen, (C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 6-18 )polycycloalkyl, (C 6-18 )polycycloalkyl(C 1-8 )alkyl-, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, —NR 7 R 8 , (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, (C 5-10 )heteroaryl(C 1-8 )alkyl-, —(C 2-4 —Y) q —(CH 2 ) 2-4 —X 1 , —C(O)R 6 , —CO 2 R 6 , —C(O)NR 7 R 8 or —S(O) 2 —NR 7 R 8 ; or R 4 and R 5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7 or 8, ring atoms and optionally consisting of 1, 2, 3 or 4 heteroatoms selected from non-peroxide oxy, —S—, sulfinyl, sulfonyl and —NH— in the ring, and wherein the ring is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
R 6 is hydrogen, (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl or (C 4-10 )heteroaryl(C 1-8 )alkyl-; wherein the heterocyclyl, heteroaryl or aryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, (C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
wherein R 7 and R 8 are independently hydrogen, (C 1-8 )alkyl, R a O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl; —COOR b , —C(O)R b or —C(O)NR b R c wherein the heterocyclyl, heteroaryl or aryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7 or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally consisting of 1, 2, 3 or 4 heteroatoms selected from non-peroxide oxy, —S—, sulfinyl, sulfonyl or —N(R b )— in the ring;
X 1 is —OR 6 , —C(O)R 6 , —CO 2 R 6 or —NR 7 R 8 ;
and Y is oxy, —S—, sulfinyl, sulfonyl and —NH—; and q is 1, 2, 3 or 4.
11. The compound of claim 1 , wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocyclyl or heteroaryl groups are unsubstituted or further substituted with one or more substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —N(CO)R b , —C(O)R b , —COOR b and —C(O)NR b R c ; wherein
R a is hydrogen, or (C 1-6 )alkyl; and R b and R c are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkyl-S—, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or thiomorpholinyl ring.
12. The compound of claim 1 wherein R is hydrogen or is selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl and halo(C 1-4 )alkyl.
13. The compound of claim 1 wherein R is selected from the group consisting of methyl, ethyl, —CH 2 —CH 2 —Cl, —CH 2 —CH 2 —Br and —CH 2 —CH 2 —CH 2 —F.
14. The compound of claim 1 wherein R 1 is hydrogen or is selected from the group consisting of (C 1-4 )alkyl, (C 3-4 )alkenyl, (C 3-8 )alkenyl(C 1-8 )alkyl, (C 3-8 )alkynyl, (C 3-8 )alkynyl(C 1-8 )alkyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, hydroxy(C 3-8 )cycloalkyl(C 1-8 )alkyl-, phenyl and phenyl(C 1-4 )alkyl.
15. The compound of claim 1 wherein R 1 is hydrogen or is selected from the group consisting of (C 3-6 )cycloalkyl, (C 3-8 )alkenyl(C 1-8 )alkyl, (C 3-8 )alkynyl(C 1-8 )alkyl, hydroxy(C 3-8 )cycloalkyl(C 1-8 )alkyl- and (C 3-6 )cycloalkyl(C 1-4 )alkyl-.
16. The compound of claim 1 wherein R 1 is selected from the group consisting of cyclopropyl, cyclopropylmethyl, cyclobutyl, hydroxycyclobutyl, trihalomethylcyclobutyl and cyclopentyl.
17. The compound of claim 1 wherein R 1 is selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, phenyl, phenethyl, benzyl and (methoxyphenyl)ethyl.
18. The compound of claim 1 wherein R 1 is selected from the group consisting of ethyl, n-propyl and allyl.
19. The compound of claim 1 wherein R 2 is hydrogen or is selected from the group consisting of (C 1-4 )alkyl, halo(C 1-8 )alkyl, (C 3-4 )alkenyl, (C 3-4 )alkynyl, phenyl, phenyl(C 1-4 )alkyl and (methoxyphenyl)ethyl.
20. The compound of claim 1 wherein R 2 is (C 3-6 )cycloalkyl, halo(C 1-8 )alkyl, or (C 3-6 )cycloalkyl(C 1-4 )alkyl-.
21. The compound of claim 1 wherein R 2 is selected from the group consisting of cyclopropyl or cyclopropylmethyl, cyclobutyl, hydroxycyclobutyl, trihalomethylcyclobutyl and cyclopentyl.
22. The compound of claim 1 wherein R 2 is selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, phenyl, phenethyl, trifluoromethylmethyl, fluoroethyl and benzyl.
23. The compound of claim 1 wherein R is hydrogen or is selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl and halo(C 1-4 )alkyl;
one of R 1 and R 2 is selected from the group consisting of cyclopropyl, and cyclopropylmethyl; and,
the other of R 1 and R 2 is hydrogen or selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, phenyl, phenethyl and benzyl.
24. The compound of claim 1 , wherein R is selected from the group consisting of methyl, ethyl, —CH 2 —CH 2 —Cl, —CH 2 —CH 2 —Br and —CH 2 —CH 2 —CH 2 —F;
one of R 1 and R 2 is selected from the group consisting of cyclopropyl, cyclopropylmethyl, cyclobutyl, hydroxycyclobutyl, trihalomethylcyclobutyl, cyclopentyl; and,
the other of R 1 and R 2 is hydrogen or selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, (methoxyphenyl)ethyl, cyclobutyl, hydroxycyclobutyl, trihalomethylcyclobutyl, cyclopentyl, trifluoromethylmethyl and fluoroethyl.
25. The compound of claim 1 , wherein Z 1 is substituted by a substituent selected from the group consisting of —OH, —O(C 1-4 )alkyl, —OC(O)NR 7 R 8 , (C 1-4 )alkyl, —NR 4 R 5 , F, Cl, Br, I, nitro, cyano, trifluoromethyl, —CO 2 R 6 and —NC(O)R 6 ;
R 4 and R 5 are each independently hydrogen or are selected from the group consisting of (C 1-6 )alkyl, (C 3-6 )cycloalkyl, (C 3-6 )heterocyclyl, (C 6-10 )aryl, (C 7-12 )aralkyl, (C 5-6 )heteroaryl, or (C 5-6 )heteroaryl(C 1-4 )alkyl, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 and —C(O)NR 6 R 7 ;
R 6 is hydrogen, (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl or (C 4-10 )heteroaryl(C 1-8 )alkyl-; wherein the heterocyclyl, heteroaryl or aryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, (C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ; and,
R 7 and R 8 are each independently hydrogen, (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl; —COOR b , —C(O)R b or —C(O)NR b R c wherein the heterocyclyl, heteroaryl or aryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7 or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally consisting of 1, 2, 3 or 4 heteroatoms selected from non-peroxide oxy, —S—, sulfinyl, sulfonyl or NH in the ring.
26. The compound of claim 25 , wherein Z 1 is substituted by one —NR 4 R 5 .
27. The compound of claim 26 , wherein R 4 and R 5 together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or thiomorpholinyl ring, wherein the ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
R a is hydrogen, or (C 1-6 )alkyl; and,
R b and R c are each independently hydrogen, or are selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkylthio, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or a thiomorpholinyl ring.
28. The compound of claim 26 , wherein R 4 and R 5 are each independently hydrogen or are independently selected from the group consisting of (C 1-4 )alkyl, hydroxy(C 2-4 )alkyl, (C 3-6 )cycloalkyl, (C 6-10 )aryl, (C 7-10 )aralkyl, (C 5-6 )heteroaryl, —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—OR b , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—COOR b , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—NR b R c , —NR 7 R 8 , —C(O)R 6 , —CO 2 R 6 and —C(O)NR 7 R 8 ;
R b and R c are each independently hydrogen, or are selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkylthio, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or a thiomorpholinyl ring; and,
q is 1, 2, 3or 4.
29. The compound of claim 26 , wherein R 4 and R 5 are each independently selected from the group consisting of methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 and —C(O)NHR 7 .
30. The compound of claim 1 , wherein:
R is hydrogen, methyl or ethyl;
one of R 1 and R 2 is selected from the group consisting of cyclopropyl, cyclopropylmethyl, cyclobutyl, hydroxycyclobutyl, trihalomethylcyclobutyl, and cyclopentyl;
the other of R 1 and R 2 is selected from the group consisting of methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, cyclobutyl, hydroxycyclobutyl, trihalomethylcyclobutyl, cyclopentyl, trifluoromethylmethyl, fluoroethyl and i-butyl;
Z 1 is (C 4-10 )heterocyclyl wherein the heterocyclyl is unsubstituted or substituted with 1, 2 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
R a is hydrogen, or (C 1-6 )alkyl; and,
R b and R c are each independently hydrogen, or are selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkylthio, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or a thiomorpholinyl ring.
31. The compound of claim 1 , wherein each substituent is independently selected from the group consisting of —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —N(CO)R b , —C(O)R b , —COOR b and —C(O)NR b R c ; wherein R a is hydrogen, or (C 1-6 )alkyl; and,
R b and R c are each independently hydrogen, or are selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkyl-S—, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or a thiomorpholinyl ring.
32. The compound of claim 1 wherein Z and Z 1 are substituted by at least one substituent selected from the group consisting of —OR 3 , —SR 3 , halo, hydroxy, —S(O)—NR 4 R 5 , —S(O) 2 —NR 4 R 5 , —NR 4 R 5 and (C 4-10 )heterocyclyl wherein the heterocyclyl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 1-8 )alkyl, (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
R 3 is selected from the group consisting of (C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, (C 5-10 )heteroaryl(C 1-8 )alkyl-, —C(O)R 6 and —C(O)NR 7 R 8 ;
R 4 and R 5 are each independently hydrogen, or are each independently selected from the group consisting of (C 1-8 )alkyl, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 1-8 )alkoxy, (C 3-8 )cycloalkyl, (C 3-8 )cycloalkyl(C 1-8 )alkyl-, (C 6-18 )polycycloalkyl, (C 6-18 )polycycloalkyl(C 1-8 )alkyl-, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, —NR 7 R 8 , (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 5-10 )heteroaryl, (C 5-10 )heteroaryl(C 1-8 )alkyl-, —(C 2-4 —Y) q —(CH 2 ) 2-4 —X 1 , —C(O)R 6 , —CO 2 R 6 , —C(O)NR 7 R 8 and —S(O) 2 —NR 7 R 8 ; or R 4 and R 5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7 or 8, ring atoms and optionally consisting of 1, 2, 3 or 4 heteroatoms selected from non-peroxide oxy, —S—, sulfinyl, sulfonyl and —N(R 9 )— in the ring, and wherein the ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
X 1 is —OR 6 , —C(O)R 6 , —CO 2 R 6 or —NR 7 R 8 ; and Y is oxy, —S—, sulfinyl, sulfonyl and —N(R 9 )—;
wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocyclyl or heteroaryl groups of R 1 , R 2 , R 3 , R 4 and R 5 groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —N(CO)R b , —C(O)R b , —COOR b and —C(O)NR b R c ;
wherein R 6 is hydrogen, or is selected from the group consisting of (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 3-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl and (C 4-10 )heteroaryl(C 1-8 )alkyl-; wherein the heterocyclyl, heteroaryl or aryl are unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, (C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ;
wherein R 7 , R 8 and R 9 are each independently hydrogen, or are each independently selected from the group consisting of (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl; —COOR b , —C(O)R b or —C(O)NR b R c wherein the heterocyclyl, heteroaryl or aryl are unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 )aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic or aromatic ring having 3, 4, 5, 6, 7 or 8 ring atoms and optionally consisting of 1, 2, 3 or 4 heteroatoms selected from non-peroxide oxy, —S—, sulfinyl, sulfonyl or amine —N(R b )— in the ring;
R a is hydrogen or (C 1-6 )alkyl;
R b and R c are each independently hydrogen, or are selected from the group consisting of (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkyl-S—, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or thiomorpholinyl ring; and,
q is 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
33. The compound of claim 1 wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocyclyl or heteroaryl groups are unsubstituted or substituted with one or more substituents independently selected from the group consisting of (C 1-5 )alkyl, (C 1-5 )alkoxy, aryloxy, heteroaryloxy, amino, halo, hydroxy, cyano, and nitro groups.
34. The compound of claim 1 , wherein the substituent on Z 1 is selected from the group consisting of:
R 4 is hydrogen or selected from the group consisting of (C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 1-8 )alkylC(O)—, (C 3-8 )alkenyl, (C 3-8 )alkynyl, (C 3-6 )cycloalkyl(C 1-8 )alkyl-, (C 4-10 )heterocyclyl, (C 4-10 )heterocyclyl(C 1-8 )alkyl-, (C 6-10 )aryl(C 1-8 )alkyl-, and (C 5-10 )heteroaryl(C 1-8 )alkyl-;
R 7 and R 8 are each independently hydrogen, (C 1-8 )alkyl, R b O(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, (C 3-10 )heterocyclyl, (C 6-10 )aryl, (C 6-10 )aryl(C 1-8 )alkyl-, (C 4-10 )heteroaryl; —COOR b , —C(O)R b or —C(O)NR b R c wherein the heterocyclyl, heteroaryl or aryl are optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, hydroxy, cyano, nitro, —OR a , —SR a , (C 6-10 aryl, —O(C 6-10 )aryl, hydroxy(C 1-8 )alkyl, R b R c N(C 1-8 )alkyl, halo(C 1-8 )alkyl, —NR b R c , —C(O)R b , —COOR b and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7 or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally consisting of 1, 2, 3 or 4 heteroatoms selected from non-peroxide oxy, —S—, sulfinyl, sulfonyl or —NH— in the ring;
R a is hydrogen, or (C 1-6 )alkyl; R b and R c are each independently hydrogen, (C 1-6 )alkyl, (C 1-6 )alkoxy, (C 3-8 )cycloalkyl, (C 1-6 )alkylthio, (C 6-10 )aryl, (C 6-10 )aryl(C 1-6 )alkyl-, heteroaryl or heteroaryl(C 1-6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl or thiomorpholinyl ring; and,
q is 1, 2, 3or 4.
35. The compound of claim 1 , wherein —Z 1 is selected from the group consisting of:
36. The compound of claim 1 , wherein R 1 is cyclopropyl, R 2 is n-propyl; R is hydrogen and m is zero.
37. The compound of claim 1 , wherein —Z 1 is selected from the group consisting of:
38. A pharmaceutical composition comprising:
(a) a therapeutically effective amount of a compound of claim 1 ; and
(b) a pharmaceutically acceptable excipient.
39. A method for treating asthma comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.
40. A method for improving insulin sensitivity comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.