Imidazolidinone compounds useful as β-secretase inhibitors for the treatment of Alzheimer's disease
View Patent ↗The present invention is directed to imidazolidinone compounds which are inhibitors of the beta-secretase enzyme and that are useful in the treatment of diseases in which the beta-secretase enzyme is involved, such as Alzheimer's disease. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the treatment of such diseases in which the beta-secretase enzyme is involved.
1. A compound of formula (I):
wherein R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl,
(5) —C 6-10 aryl, or
(6) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(c) —C 3-12 cycloalkyl,
(d) —OH,
(e) —CN,
(f) —O—C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(g) —C 6-10 aryl, or
(h) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) -Q 1 -C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(v) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vi) —C 3-12 cycloalkyl,
and Q 1 is selected from the group consisting of
(A) —O—,
(B) —SO 2 —,
(C) —NH—,
or R 2 and R 3 are linked together to form a 3-7 carbocyclic ring structure, wherein one, two or three of the ring carbon atoms may be replaced with O, S, NH, —C(═O)— or SO 2 , and the carbocyclic ring is optionally substituted with one or more
(a) —C 1-10 alkyl,
(b) —C 2-10 alkenyl,
(c) —C 2-10 alkynyl, and
(d) —C 6-10 aryl;
X is selected from the group consisting of
(1)-(Q 2 ) n -R 5 ,
wherein Q 2 is selected from the group consisting of
(a) —CH 2 —, and
(b) —O—,
R 5 is selected from the group consisting of
(a) hydrogen
(b) —C 1-10 alkyl,
(c) —C 2-10 alkenyl,
(d) —C 2-10 alkynyl, and
(e) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(iii) —C 3-12 cycloalkyl,
(iv) —OH,
(v) —CN,
(vi) —O—C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vii) —C 6-10 aryl; and
wherein R 6 is selected from the group consisting of
(a) (R 8 —SO 2 )N(R 9 )—, wherein R 8 is selected from the group consisting of
(i) —C 1-10 alkyl,
(ii) —C 2-10 alkenyl,
(iii) —C 2-10 alkynyl,
(iv) —C 3-8 cycloalkyl, or
(v) —C 6-10 aryl
wherein said alkyl, alkenyl, alkynyl, cycloalkyl and aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O—C 1-10 alkyl,
(E) —C 1-10 alkyl,
(F) —C 2-10 alkenyl,
(G) —C 2-10 alkynyl,
(H) —C 3-8 cycloalkyl,
(I) —C 6-10 aryl, or
(J) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(I) halo,
(II) —OH,
(III) —CN,
(IV) —O—C 1-10 alkyl,
(V) —C 3-8 cycloalkyl,
(VI) —C 1-10 alkyl,
(VII) —C 2-10 alkenyl, or
(VIII) —C 2-10 alkynyl;
R 9 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, or
(v) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O—C 1-10 alkyl,
(E) —C 3-8 cycloalkyl,
(F) —C 6-10 aryl, or
(G) heteroaryl,
wherein said cycloalkyl, aryl or heteroaryl is optionally substituted with one or more
(I) halo,
(II) —OH,
(III) —CN,
(IV) —O—C 1-10 alkyl,
(V) —C 3-8 cycloalkyl, or
(VI) —C 6-10 aryl;
(b)
(c)
and R 7 is selected from the group consisting of
wherein R 10 is C 1-10 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen;
R 11a , R 11b , and R 11c are independently selected from the group consisting of:
(i) hydrogen,
(ii) halo,
(iii) —C 1-10 alkyl,
(iv) —OH,
(v) —CN,
(vi) —C 3-12 cycloalkyl, and
(vii) —O—C 1-10 alkyl;
R 12 and R 13 are independently selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, and
(v) —C 1-10 alkyl-C 3-12 cycloalkyl;
wherein said alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —C 1-10 alkyl,
(E) —O—C 1-10 alkyl,
(F) —C 3-8 cycloalkyl,
(G) —NR a R b , wherein R a and R b are selected from the group consisting of
(i) hydrogen, and
(ii) —C 1-10 alkyl, or R a and R b are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, or
(H) —C 6-10 aryl;
or R 12 and R 13 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, wherein said carbocyclic ring is optionally substituted with one or more
(1) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more
(i) halogen,
(ii) hydroxy, or
(iii) —C 1-6 alkoxy;
(2) —C 3-12 cycloalkyl,
(3) (CH 2 ) m -phenyl, wherein said phenyl is unsubstituted or substituted with one or more halogen,
(4) C 2-10 alkenyl,
(5) C 2-10 alkynyl,
(6) —CN,
and said alkyl, alkenyl or alkynyl R12 and R 13 groups are optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —O—C 1-10 alkyl, or
(e) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl R 12 and R 13 groups are optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl,
(c) OH,
(d) —CN,
(e) —C 3-12 cycloalkyl, or
(f) —O—C 1-10 alkyl;
R 14 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl;
(iii) halo,
(iv) —C 3-12 cycloalkyl,
(v) —C 6-10 aryl, and
(vi) heteroaryl,
wherein said aryl and heteroaryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O—C 1-10 alkyl,
(E) —C 3-8 cycloalkyl, or
(F) —C 1-10 alkyl;
wherein Y is R 6 or halogen,
and R 15 and R 16 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl, and
(5) —C 1-10 alkylene-C 3-12 cycloalkyl;
wherein said alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl
(e) —C 3-12 cycloalkyl,
(f) —O—C 1-10 alkyl,
(g) heteroaryl, wherein said heteroaryl may be unsubstituted or substituted with halogen;
(h) phenyl, or
(i) —NR c R d ,
(I) hydrogen, and
(II) —C 1-10 alkyl, or R c and R d are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen,
or R 15 and R 16 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitorgen, wherein said carbocyclic ring is unsubstituted or substituted with one or more
(a) —C 1-10 alkyl,
(b) —C 3-12 cycloalkyl,
(c) —(CH 2 ) n -phenyl,
(d) —C 2-10 alkenyl, or
(e) —C 2-10 alkynyl,
wherein said alkyl, alkenyl and alkynyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O—C 1-10 alkyl, or
(v) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl,
(iii) —OH,
(iv) —CN,
(v) —C 3-12 cycloalkyl, or
(vi) —O—C 1-10 alkyl;
m is 0, 1, 2, 3 or 4;
n is 0 or 1; and
p is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.
2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of C 1-10 alkyl, wherein the alkyl is optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl,
(c) —O—C 1-10 alkyl,
(d) —C 6-10 aryl, or
(e) heteroaryl,
and said aryl or heteroaryl is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) -Q 1 -C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(v) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
and Q1 is selected from the group consisting of
(A) —O—, or
(B) —SO 2 —.
3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, and R 3 is C 1-10 alkyl or C 6-10 aryl.
4. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each C 1-10 alkyl.
5. A compound of any of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are linked together to form a 3-7 carbocyclic ring structure, wherein one, two or three of the ring carbon atoms may be replaced with O, S, NH, —C(═O)— or SO 2 , and the carbocyclic ring is optionally substituted with C 1-10 alkyl.
6. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of
(1)—C 1-10 alkyl,
(2) phenyl, and
(3) heteroaryl,
wherein said alkyl, phenyl or heteroaryl are optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) -Q 1 -C 1-10 alkyl,
(v) —C 1-10 alkyl, or
(vi) —C 3-12 cycloalkyl.
7. A compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 4 is phenyl.
8. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 15 is C 1-6 alkyl and R 16 is C 1-6 alkyl-C 3-12 cycloalkyl.
10. A compound of claim 1 , which is a compound of formula II
or a pharmaceutically acceptable salt thereof, and individual enantiomers and diasteromers thereof.
11. A compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein Q 2 is —O—and R 5 is C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl, or
(vii) —C 6-10 aryl.
12. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of formula (III):
or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.
13. A compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 6 is (R 8 —SO 2 )N(R 9 )—.
14. A compound of which is selected from the group consisting of:
tert-Butyl (1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-1-(1-methylbutyl)-5-oxoimidazolidin-4-yl]ethylcarbamic acid;
tert-Butyl (1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-1-isopentyl-2-isopropyl-5-oxoimidazolidin-4-yl]ethylcarbamic acid;
tert-Butyl (1S,2R)-1-benzyl-2-hydroxy-2-{(4S)-2-isopropyl-5-oxo-1-[3-(trifluoromethyl)benzyl]imidazolidin-4-yl}ethylcarbamic acid;
tert-Butyl (1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-5-oxo-1-(2-phenylethyl)imidazolidin-4-yl]ethylcarbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-5-oxo-1-pentylimidazolidin-4-yl]ethyl}carbamic acid;
[(1S,2R)-2-Hydroxy-2-[(4S)-1-[2-(1-methylethoxy)ethyl]-2-(1-methylethyl)-5-oxo-4-imidazolidinyl]-1-(phenylmethyl)ethyl]-, 1, 1-dimethylethyl ester carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-1-(2-methoxyethyl)-5-oxoimidazolidin-4-yl]ethyl}carbamic acid;
tert-Butyl ((1S,2R)-1-benzyl-2-hydroxy-2-{(4S)-2-isopropyl-5-oxo-1-[2-(trifluoromethyl)benzyl]imidazolidin-4-yl}ethyl)carbamic acid;
tert-Butyl ((1S,2R)-1-benzyl-2-hydroxy-2-{(4S)-2-isopropyl-5-oxo-1-[(1S)-1-phenylethyl]imidazolidin-4-yl}ethyl)carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-5-oxo-1-(pyridin-2-ylmethyl)imidazolidin-4-yl]ethyl}carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-5-oxo-1-(pyridin-3-ylmethyl)imidazolidin-4-yl]ethyl}carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-5-oxo-1-(pyridin-4-ylmethyl)imidazolidin-4-yl]ethyl}carbamic acid;
tert-Butyl ((1S,2R)-1-benzyl-2-{(4S)-1-[(1R)-1,5-dimethylhexyl]-2-isopropyl-5-oxoimidazolidin-4-yl}-2-hydroxyethyl)carbamic acid;
tert-Butyl ((1S,2R)-1-benzyl-2-{(4S)-1-[(1S)-1,5-dimethylhexyl]-2-isopropyl-5-oxoimidazolidin-4-yl}-2-hydroxyethyl)carbamic acid;
tert-Butyl ((1S,2R)-1-benzyl-2-hydroxy-2-{(4S)-2-isopropyl-1-[4-(methylsulfonyl)benzyl]-5-oxoimidazolidin-4-yl}ethyl)carbamic acid;
tert-Butyl ((1S,2R)-2-{(4S)-1-[2-(1,3-benzodioxol-5-yl)ethyl]-2-isopropyl-5-oxoimidazolidin-4-yl}-1-benzyl-2-hydroxyethyl)carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-hydroxy-2-[(4S)-2-isopropyl-5-oxo-1-(1-propylbutyl)imidazolidin-4-yl]ethyl}carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-[(4S)-1-(3-fluorobenzyl)-2-isopropyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
tert-Butyl {(1,2R)-1-benzyl-2-[(4S)-1-(4-fluorobenzyl)-2-isopropyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
tert-Butyl ((1S,2R)-1-benzyl-2-hydroxy-2-{(4S)-2-isopropyl-5-oxo-1-[3-(trifluoromethoxy)benzyl]imidazolidin-4-yl}ethyl)carbamic acid;
tert-Butyl ((1S,2R)-1-benzyl-2-{(4S)-1-[2-fluoro-4-(trifluoromethyl)benzyl]-2-isopropyl-5-oxoimidazolidin-4-yl}-2-hydroxyethyl)carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-[(2S,4S)-1-benzyl-2-ethyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-[(4S)-1-benzyl-2-methyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-[(4S)-1-benzyl-5-oxo-2-propylimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-[(4S)-1-benzyl-2-butyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
tert-Butyl {(1S,2R)-1-benzyl-2-[(4S)-1-benzyl-2-isopropyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
Phenyl {(1S,2R)-1-benzyl-2-[(4S)-1-benzyl-2-isopropyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
Phenyl {(1S,2R)-1-benzyl-2-[(2S,4S)-1-benzyl-2-butyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
Phenyl {(1S,2R)-1-benzyl-2-[(6S)-8-benzyl-7-oxo-5,8-diazaspiro[3.4]oct-6-yl]-2-hydroxyethyl}carbamic acid;
Phenyl {(1S,2R)-1-benzyl-2-[(2S)-4-benzyl-3-oxo-8-oxa-1,4-diazaspiro[4.5]dec-2-yl]-2-hydroxyethyl}carbamic acid;
Phenyl {(1S,2R)-1-benzyl-2-[(2S)-4-benzyl-8-methyl-3-oxo-1,4-diazaspiro[4.5]dec-2-yl]-2-hydroxyethyl}carbamic acid
Phenyl {(1S,2R)-1-benzyl-2-[(4S)-1-benzyl-2,2-dibutyl-5-oxoimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
Phenyl {(1S,2R)-1-benzyl-2-[(2S)-4-benzyl-3-oxo-1,4-diazaspiro[4.4]non-2-yl]-2-ydroxyethyl}carbamic acid;
Phenyl {(1S,2R)-1-benzyl-2-[(4S)-1-benzyl-5-oxo-2-phenylimidazolidin-4-yl]-2-hydroxyethyl}carbamic acid;
Phenyl ((1S,2R)-1-benzyl-2-{(4S)-2-butyl-5-oxo-1-[(1S)-1-phenylethyl]imidazolidin-4-yl}-2-hydroxyethyl)carbamic acid;
N-[(1S)-1-Benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]-N′-[(1R)-1-(4-Fluorophenyl)ethyl]-5-[1-(methylsulfonyl)ethyl]isophthalamic acid;
N-[(1S)-1-Benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]-2-(4-butyl-2,3-dioxopiperazin-1-yl)acetamide;
N′-[(1S)-1-Benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]-N,N-dipropylisophthalamic acid;N-[(1S)-1-Benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]benzamide; N-[(1S)-1-Benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]-2-phenylacetamide; tert-Butyl [(1S)-1-benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]carbamic acid; Phenyl [(1S)-1-benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]carbamic acid;
N-[(1S)-1-benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]acetamide;
tert-Butyl [(1S)-1-benzyl-2-(1-benzyl-2-methyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]carbamic acid;
tert-Butyl3-benzyl-5-{(2S)-2-[(tert-butoxycarbonyl)amino]-1-hydroxy-3-phenylpropyl }-2-methyl-4-oxoimidazolidine-1-carboxylic acid; N-[(1S)-1-Benzyl-2-(1-benzyl-2-methyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]-N′-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]isophthalamic acid;
Phenyl[(1S)-1-benzyl-2-(1-benzyl-2-methyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]carbamic acid;
N-{(1S,2S)-1-Benzyl-2-hydroxy-2-[(4S)-1,2,2-trimethyl-5-oxoimidazolidin-4-yl]ethyl}-N′-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]isophthalamic acid;
5N-[(1S)-1-benzyl-2-hydroxy-2-(1,2,2-trimethyl-5-oxoimidazolidin-4-yl)ethyl]-N′-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]isophthalamic acid;
N-[(1S)-1-benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]-2-chloro-6-(methyl{[(1S,2S)-2-methylcyclopropyl]methyl}amino)isonicotinamide;
N-[(1S)-1-benzyl-2-(1-benzyl-2,2-dimethyl-5-oxoimidazolidin-4-yl)-2-hydroxyethyl]-2-(methyl{[(1S,2S)-2-methylcyclopropyl]methyl }amino)-6-[methyl(methylsulfonyl)amino]isonicotinamide;
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
16. A method for treating Alzheimer's disease in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
17. A compound of formula (I):
wherein:
R 2 is hydrogen;
R 3 is C 1-10 alkyl or C 6-10 aryl;
R 1 and R 4 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl,
(5) —C 6-10 aryl, or
(6) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(c) —C 3-12 cycloalkyl,
(d) —OH,
(e) —CN,
(f) —O-C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(g) —C 6-10 aryl, or
(h) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —Q 1 -C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(v) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vi) —C 3-12 cycloalkyl,
and Q 1 is selected from the group consisting of
(A) —O—,
(B) —SO 2 —,
(C) —NH—,
to form a 3-7 carbocyclic ring structure, wherein one, two or three of the ring carbon atoms may be replaced with O, S, NH, —C(=O)— or SO 2 , and the carbocyclic ring is optionally substituted with one or more
(a) —C 1-10 alkyl,
(b) —C 2-1 alkenyl,
(c) —C 2-10 alkynyl, and
X is selected from the group consisting of
(1) —(Q 2 ) n —R 5 ,
wherein Q 2 is selected from the group consisting of
(a) —CH 2 —, and
(b) —O—,
R 5 is selected from the group consisting of
(a) hydrogen
(b) —C 1-10 alkyl,
(c) —C 2-10 alkenyl,
(d) —C 2-10 alkynyl, and
(e) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(iii) —C 3-12 cycloalkyl,
(iv) —OH,
(v) —CN,
(vi) —O-C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vii) —C 6-10 aryl; and
wherein R6 is selected from the group consisting of
(a) (R 8 —SO 2 )N(R 9 )—, wherein R 8 is selected from the group consisting of
(i) —C 1-10 alkyl,
(ii) —C 2-10 alkenyl,
(iii) —C 2-10 alkynyl,
(iv) —C 3-8 cycloalkyl, or
(v) —C 6-10 aryl
wherein said alkyl, alkenyl, alkynyl, cycloalkyl and aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 1-10 alkyl,
(F) —C 2-10 alkenyl,
(G) —C 2-10 alkynyl,
(H) —C 3-8 cycloalkyl,
(I) —C 6-10 aryl, or
(J) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(I) halo,
(II) —OH,
(III) —CN,
(IV) —O-C 1-10 alkyl,
(V) —C 3-8 cycloalkyl,
(VI) —C 1-10 alkyl,
(VII) —C 2-10 alkenyl, or
(VIII) —C 2-10 alkynyl;
R 9 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, or
(v) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 3-8 cycloalkyl,
(F) —C 6-10 aryl, or
(G) heteroaryl,
wherein said cycloalkyl, aryl or heteroaryl is optionally substituted with one or more
(I) halo,
(II) —OH,
(III) —CN,
(IV) —O-C 1-10 alkyl,
(V) —C 3-8 cycloalkyl, or
(VI) —C 6-10 aryl;
(d) hydrogen;
and R 7 is selected from the group consisting of
wherein R 10 is C 1-10 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen;
R 11a , R 11b , and R 11c are independently selected from the group consisting of:
(i) hydrogen,
(ii) halo,
(iii) —C 1-10 alkyl,
(iv) —OH,
(v) —CN,
(vi) —C 3-12 cycloalkyl, and
(vii) —O-C 1-10 alkyl;
R 12 and R 13 are independently selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, and
(v) —C 1-10 alkyl-C 3-12 cycloalkyl;
wherein said alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —C 1-10 alkyl,
(E) —O-C 1-10 alkyl,
(F) —C 3-8 cycloalkyl,
(G) NR a R b , wherein R a and R b are selected from the group consisting of
(i) hydrogen, and
(ii) —C 1-10 alkyl, or R a and R b are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, or
(H) —C 6-10 aryl;
or R 12 and R 13 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, wherein said carbocyclic ring is optionally substituted with one or more
(1) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more
(i) halogen,
(ii) hydroxy, or
(iii) —C 1-6 alkoxy;
(2) —C 3-12 cycloalkyl,
(3) (CH 2 ) m -phenyl, wherein said phenyl is unsubstituted or substituted with one or more halogen,
(4) C 2-10 alkenyl,
(5) C 2-10 alkynyl,
(6) —CN,
and said alkyl, alkenyl or alkynyl R 12 and R 13 groups are optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —O-C 1-10 alkyl, or
(e) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl R 12 and R 1 3 groups are optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl,
(c) OH,
(d) —CN,
(e) —C 3-12 cycloalkyl, or
(f) —O-C 1-10 alkyl;
R 14 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl;
(iii) halo,
(iv) —C 3-12 cycloalkyl,
(v) —C 6-10 aryl, and
(vi) heteroaryl,
wherein said aryl and heteroaryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 3-8 cycloalkyl, or
(F) —C 1-10 alkyl;
wherein Y is R 6 or halogen,
and R 15 and R 16 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl, and
(5) —C 1-10 alkylene—C 3-12 cycloalkyl;
wherein said alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl
(e) —C 3-12 cycloalkyl,
(f) —O-C 1-10 alkyl,
(g) heteroaryl, wherein said heteroaryl may be unsubstituted or substituted with halogen;
(h) phenyl, or
(i) —NR c R d ,
(I) hydrogen, and
(II) —C 1-10 alkyl, or Rhu c and R d are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen,
or R 15 and R 16 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitorgen, wherein said carbocyclic ring is unsubstituted or substituted with one or
more
(a) —C 1-10 alkyl,
(b) —C 3-12 cycloalkyl,
(c) —(CH 2 ) n -phenyl,
(d) —C 2-10 alkenyl, or
(e) —C 2-10 alkynyl,
wherein said alkyl, alkenyl and alkynyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O-C 1-10 alkyl, or
(v) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl,
(iii) —OH,
(iv) —CN,
(v) —C 3-12 cycloalkyl, or
(vi) —O-C 1-10 alkyl;
m is 0, 1, 2, 3 or 4;
n is 0 or 1; and
p is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.
18. A compound of formula (I):
wherein:
R 2 and R 3 are each —C 1-10 alkyl;
R 1 and R 4 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl,
(5) —C 6-10 aryl, or
(6) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(c) —C 3-12 cycloalkyl,
(d) —OH,
(e) —CN,
(f) —O-C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(g) —C 6-10 aryl, or
(h) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —Q 1 —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(v) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vi) —C 3-12 cycloalkyl,
and Q 1 is selected from the group consisting of
(A) —O—,
(B) —SO 2 —,
(C) —NH—,
to form a 3-7 carbocyclic ring structure, wherein one, two or three of the ring carbon atoms may be replaced with O, S, NH, —C(=O)— or SO 2 , and the carbocyclic ring is optionally substituted with one or more
(a) —C 1-10 alkyl,
(b) —C 2-10 alkenyl,
(c) —C 2-10 alkynyl, and
X is selected from the group consisting of
(1) —(Q 2 ) n —R 5 ,
wherein Q 2 is selected from the group consisting of
(a) —CH 2 —, and
(b) —O—,
R 5 is selected from the group consisting of
(a) hydrogen
(b) —C 1-10 alkyl,
(c) —C 2-10 alkenyl,
(d) —C 2-10 alkynyl, and
(e) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(iii) —C 3-12 cycloalkyl,
(iv) —OH,
(v) —CN,
(vi) —O-C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vii) —C 6-10 aryl; and
wherein R 6 is selected from the group consisting of
(a) (R 8 —SO 2 )N(R 9 )—, wherein R 8 is selected from the group consisting of
(i) —C 1-10 alkyl,
(ii) —C 2-10 alkenyl,
(iii) —C 2-10 alkynyl,
(iv) —C 3-12 cycloalkyl, or
(v) —C 6-10 aryl
wherein said alkyl, alkenyl, alkynyl, cycloalkyl and aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 1-10 alkyl,
(F) —C 2-10 alkenyl,
(G) —C 2-10 alkynyl,
(H) —C 3-8 cycloalkyl,
(I) —C 6-10 aryl, or
(J) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(1) halo,
(II) —OH,
(III) —CN,
(IV) —O-C 1-10 alkyl,
(V) —C 3-8 cycloalkyl,
(VI) —C 1-10 alkyl,
(VII) —C 2-10 alkenyl, or
(VIII) —C 2-10 alkynyl;
R 9 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, or
(v) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 3-8 cycloalkyl,
(F) —C 6-10 aryl, or
(G) heteroaryl,
wherein said cycloalkyl, aryl or heteroaryl is optionally substituted with one or more
(1) halo,
(II) —OH,
(DI) —CN,
(IV) —O-C 1-10 alkyl,
(V) —C 3-8 cycloalkyl, or
(VI) —C 6-10 aryl;
(d) hydrogen;
and R 7 is selected from the group consisting of
wherein R 10 is C 1-10 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen;
R 11a , R 11b , and R 11c are independently selected from the group consisting of:
(i) hydrogen,
(ii) halo,
(iii) —C 1-10 alkyl,
(iv) —OH,
(v) —CN,
(vi) —C 3-12 cycloalkyl, and
(vii) —O-C 1-10 alkyl;
R 12 and R 13 are independently selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, and
(v) —C 1-10 alkyl—C 3-12 cycloalkyl;
wherein said alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —C 1-10 alkyl,
(E) —O-C 1-10 alkyl,
(F) —C 3-8 cycloalkyl,
(G) —NR a R b , wherein R a and R b are selected from the group consisting of
(i) hydrogen, and
(ii) —C 1-10 alkyl, or R a and R b are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, or
(H) —C 6-10 aryl;
or R 12 and R 13 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, wherein said carbocyclic ring is optionally substituted with one or more
(1) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more
(i) halogen,
(ii) hydroxy, or
(iii) —C 1-6 alkoxy;
(2) —C 3-12 cycloalkyl,
(3) (CH 2 ) m -phenyl, wherein said phenyl is unsubstituted or substituted with one or more halogen,
(4) C 2-10 alkenyl,
(5) C 2-10 alkynyl,
(6) —CN,
and said alkyl, alkenyl or alkynyl R 12 and R 13 groups are optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —O-C 1-10 alkyl, or
(e) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl R 12 and R 13 groups are optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl,
(c) OH,
(d) —CN,
(e) —C 3-12 cycloalkyl, or
(f) —O-C 1-10 alkyl;
R 14 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl;
(iii) halo,
(iv) —C 3-12 cycloalkyl,
(v) —C 6-10 aryl, and
(vi) heteroaryl,
wherein said aryl and heteroaryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 3-8 cycloalkyl, or
(F) —C 1-10 alkyl;
wherein Y is R 6 or halogen,
and R 15 and R 16 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl, and
(5) —C 1-10 alkylene—C 3-12 cycloalkyl;
wherein said alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl
(e) —C 3-12 cycloalkyl,
(f) —O-C 1-10 alkyl,
(g) heteroaryl, wherein said heteroaryl may be unsubstituted or substituted with halogen;
(h) phenyl, or
(i) —NR c R d ,
(I) hydrogen, and
(II) —C 1-10 alkyl, or R c and R d are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen,
or R 15 and R 16 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitorgen, wherein said carbocyclic ring is unsubstituted or substituted with one or
more
(a) —C 1-10 alkyl,
(b) —C 3-12 cycloalkyl,
(c) —(CH 2 ) n -phenyl,
(d) —C 2-10 alkenyl, or
(e) —C 2-10 alkynyl,
wherein said alkyl, alkenyl and alkynyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O-C 1-10 alkyl, or
(v) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl,
(iii) —OH,
(iv) —CN,
(v) —C 3-12 cycloalkyl, or
(vi) —O-C 1-10 alkyl;
m is 0, 1, 2, 3 or 4;
n is 0 or 1; and
p is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.
19. A compound of formula (I):
wherein:
R 2 and R 3 are linked together to form a 3-7 carbocyclic ring structure, wherein one, two or three of the ring carbon atoms may be replaced with O, S, NH, —C(=O)— or SO 2 , and the carbocyclic ring is optionally substituted with C 1-10 alkyl;
R 1 and R 4 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
(3) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl,
(5) —C 6-10 aryl, or
(6) heteroaryl,
wherein said alkyl, alkenyl, alkynyl, aryl or heteroaryl is optionally substituted with one or more
(a) halo,
(b) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(c) —C 3-12 cycloalkyl,
(d) —OH,
(e) —CN,
(f) —O-C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(g) —C 6-10 aryl, or
(h) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —Q 1 —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(v) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vi) —C 3-12 cycloalkyl, and Q 1 is selected from the group consisting of
(A) —O—,
(B) —SO 2 —,
(C) —NH—,
to form a 3-7 carbocyclic ring structure, wherein one, two or three of the ring carbon atoms may be replaced with O, S, NH, —C(=O)— or SO 2 , and the carbocyclic ring is optionally substituted with one or more
(a) —C 1-10 alkyl,
(b) —C 2-10 alkenyl,
(c) —C 2-10 alkynyl, and
X is selected from the group consisting of
(1) —(Q 2 ) n —R 5 ,
wherein Q 2 is selected from the group consisting of
(a) —CH 2 —, and
(b) —O—,
R 5 is selected from the group consisting of
(a) hydrogen
(b) —C 1-10 alkyl,
(c) —C 2-10 alkenyl,
(d) —C 2-10 alkynyl, and
(e) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro,
(iii) —C 3-12 cycloalkyl,
(iv) —OH,
(v) —CN,
(vi) —O-C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more fluoro, or
(vii) —C 6-10 aryl; and
wherein R 6 is selected from the group consisting of
(a) (R 8 -SOhd 2 )N(R 9 )—, wherein R 8 is selected from the group consisting of
(i) —C 1-10 alkyl,
(ii) —C 2-10 alkenyl,
(iii) —C 2-10 alkynyl,
(iv) —C 3-8 cycloalkyl, or
(v) —C 6-10 aryl
wherein said alkyl, alkenyl, alkynyl, cycloalkyl and aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 1-10 alkyl,
(F) —C 2-10 alkenyl,
(G) —C 2-10 alkynyl,
(H) —C 3-8 cycloalkyl,
(I) —C 6-10 aryl, or
(J) heteroaryl,
and said aryl and heteroaryl is optionally substituted with one or more
(I) halo,
(II) —OH,
(III) —CN,
(IV) —O-C 1-10 alkyl,
(V) —C 3-8 cycloalkyl,
(VI) —C 1-10 alkyl,
(VII) —C 2-10 alkenyl, or
(VIII) —C 2-10 alkynyl;
R 9 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, or
(v) —C 6-10 aryl,
wherein said alkyl, alkenyl, alkynyl or aryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 3-8 cycloalkyl,
(F) —C 6-10 aryl, or
(G) heteroaryl,
wherein said cycloalkyl, aryl or heteroaryl is optionally substituted with one or more
(I) halo,
(II) —OH,
(III) —CN,
(IV) —O-C 1-10 alkyl,
(V) —C 3-8 cycloalkyl, or
(VI) —C 6-10 aryl;
(d) hydrogen;
and R 7 is selected from the group consisting of
wherein R 10 is C 1-10 alkyl, wherein said alkyl is unsubstituted or substituted with one or more halogen;
R 11a , R 11b , and R 11c are independently selected from the group consisting of
(i) hydrogen,
(ii) halo,
(iii) —C 1-10 alkyl,
(iv) —OH,
(v) —CN,
(vi) —C 3-12 cycloalkyl, and
(vii) —O-C 1-10 alkyl;
R 12 and R 13 are independently selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl,
(iii) —C 2-10 alkenyl,
(iv) —C 2-10 alkynyl, and
(v) —C 1-10 alkyl—C 3-12 cycloalkyl;
wherein said alkyl, alkenyl, alkynyl and cycloalkyl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —C 1-10 alkyl,
(E) —O-C 1-10 alkyl,
(F) —C 3-8 cycloalkyl,
(G) —NR a R b , wherein R a and R b are selected from the group consisting of
(i) hydrogen, and
(ii) —C 1-10 alkyl, or R a and R b are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, or
(H) —C 6-10 aryl;
or R 12 and R 13 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen, wherein said carbocyclic ring is optionally substituted with one or more
(1) —C 1-10 alkyl, wherein said alkyl is optionally substituted with one or more
(i) halogen,
(ii) hydroxy, or
(iii) —C 1-6 alkoxy;
(2) —C 3-12 cycloalkyl,
(3) (CH 2 ) m -phenyl, wherein said phenyl is unsubstituted or substituted with one or more halogen,
(4) C 2-10 alkenyl,
(5) C 2-10 alkynyl,
(6) —CN,
and said alkyl, alkenyl or alkynyl R 12 and R 13 groups are optionally substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl, or
(e) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl R 12 and R 13 groups are optionally substituted with one or more
(a) halo,
(b) —O-C 1-10 alkyl,
(c) OH,
(d) —CN,
(e) —C 3-12 cycloalkyl, or
(f) —O-C 1-10 alkyl;
R 14 is selected from the group consisting of
(i) hydrogen,
(ii) —C 1-10 alkyl;
(iii) halo,
(iv) —C 3-12 cycloalkyl,
(v) —C 6-10 aryl, and
(vi) heteroaryl,
wherein said aryl and heteroaryl is optionally substituted with one or more
(A) halo,
(B) —OH,
(C) —CN,
(D) —O-C 1-10 alkyl,
(E) —C 3-8 cycloalkyl, or
(F) —C 1-10 alkyl;
wherein Y is R 6 or halogen,
and R 15 and R 16 are independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-10 alkyl,
( 3 ) —C 2-10 alkenyl,
(4) —C 2-10 alkynyl, and
(5) —C 1-10 alkylene—C 3-12 cycloalkyl;
wherein said alkyl, cycloalkyl, alkenyl or alkynyl is unsubstituted or substituted with one or more
(a) halo,
(b) —OH,
(c) —CN,
(d) —C 1-10 alkyl
(e) —C 3-12 cycloalkyl,
(f) —O-C 1-10 alkyl,
(g) heteroaryl, wherein said heteroaryl may be unsubstituted or substituted with halogen;
(h) phenyl, or
(i) —NR c R d ,
(I) hydrogen, and
(II) —C 1-10 alkyl, or R c and R d are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitrogen,
or R 15 and R 16 are joined together with the nitrogen atom to which they are attached to form a 4-6 membered carbocyclic ring having a single nitorgen, wherein said carbocyclic ring is unsubstituted or substituted with one or
more
(a) —C 1-10 alkyl,
(b) —C 3-12 cycloalkyl,
(c) —(CH 2 ) n -phenyl,
(d) —C 2-10 alkenyl, or
(e) —C 2-10 alkynyl,
wherein said alkyl, alkenyl and alkynyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —OH,
(iii) —CN,
(iv) —O-C 1-10 alkyl, or
(v) —C 3-12 cycloalkyl;
and said cycloalkyl and phenyl is unsubstituted or substituted with one or more
(i) halo,
(ii) —C 1-10 alkyl,
(iii) —OH,
(iv) —CN,
(v) —C 3-12 cycloalkyl, or
(vi) —O-C 1-10 alkyl;
m is 0, 1, 2, 3 or 4;
n is 0 or 1; and
p is 1, 2, 3 or 4;
or a pharmaceutically acceptable salt thereof, and individual enantiomers and diastereomers thereof.