Substituted amides
View Patent ↗Novel compounds of the structural formula (I) are antagonists and/or inverse agonists of the Cannabinoid-1 (CB1) receptor and are useful in the treatment, prevention and suppression of diseases mediated by the CB1 receptor. The compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, migraine, neuropathy, neuro-inflammatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia. The compounds are also useful for the treatment of substance abuse disorders, the treatment of obesity or eating disorders, as well as the treatment of asthma, constipation, chronic intestinal pseudo-obstruction, and cirrhosis of the liver.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein;
R 1 is selected from:
(1) cycloheteroalkyl, and
(2) heteroaryl,
wherein each cycloheteroalkyl, and heteroaryl is optionally substituted with one to four substituents independently selected from R b ;
R 2 is aryl-C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a , and each aryl is optionally substituted with one to four substituents independently selected from R b ;
R 3 is selected from:
(1) hydrogen, and
(2) C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a ;
R 4 is selected from:
(1) hydrogen, and
(2) C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a ;
R 5 is C 1-8 alkyl substituted with —OR d , wherein R d is heteroaryl and wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;
each R a is independently selected from:
(1) —OR d ,
(2) —NR c S(O) m R d ,
(3) halogen,
(4) —SR d ,
(5) —S(O) m NR c R d ,
(6) —NR c R d ,
(7) —C(O)R d ,
(8) —CO 2 R d ,
(9) —CN,
(10) —C(O)NR c R d ,
(11) —NR c C(O)R d ,
(12) —NR c C(O)OR d ,
(3) —NR c C(O)NR c R d ,
(14) —CF 3 ,
(15) —OCF 3 , and
(16) cycloheteroalkyl;
each R b is independently selected from:
(1) —OR d ,
(2) halogen,
(3) —CN,
(4) —CF 3 ,
(5) —OCF 3 ,
(6) cycloheteroalkyl;
(7) C 1-4 alkyl,
(8) oxo,
(9) phenyl,
(10) benzyl, and
(11) heteroaryl;
each R c is independently selected from:
(1) hydrogen, and
(2) C 1-4 alkyl, and
each R d is independently selected from:
(1) hydrogen,
(2) C 1-4 alkyl,
(3) C 2-6 alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C 1-4 alkyl,
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C 1-4 alkyl,
(8) phenyl,
(9) heteroaryl,
(10) phenyl-C 1-4 alkyl, and
(11) heteroaryl-C 1-4 alkyl, or
R c and R d together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and N—R g ,
each R c and R d may be unsubstituted or substituted with one to three substituents selected from R h ;
each R g is independently selected from:
(1) C 1-4 alkyl, and
(2) —C(O)C 1-4 alkyl;
each R h is independently selected from:
(1) halogen,
(2) C 1-10 alkyl,
(3) —O C 1-4 alkyl,
(4) —S C 1-4 alkyl,
(5) —CN,
(6) —CF 3 , and
(7) —OCF 3 ,
m is selected from 1 and 2.
2. The compound according to claim 1 , wherein R 4 is selected from:
(1) hydrogen, and
(2) methyl;
and pharmaceutically acceptable salts thereof.
3. The compound according to claim 2 , wherein R 3 is selected from hydrogen, methyl and ethyl;
and pharmaceutically acceptable salts thereof.
4. The compound according to claim 3 , selected from:
(1) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;
(2) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-methyl-2-(2-pyridyloxy)propanamide;
(3) N-(2-(1-(1,2,4-triazolyl))-3-(4-chlorophenyl)-1-methylpropyl)-2-(2-pyridyloxy)-2-methylpropanamide;
(4) N-[3-(4-chlorophenyl)-2-(2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(5) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(6) N-[3 (4-chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(7) N-[3-(4-chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(8) N-[3 (4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(9) N-[3 (4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;
(10) N-[3 (4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(11) N-[3 (4-chlorophenyl)-2-(5-chloro-3-pyridyl-1-methylpropyl]-2-(6-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;
(12) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(13) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(14) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(15) N-[2 (5 bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(16) N-[2-(5-bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(17) N-[2 (5 bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(18) N-[2-(5-bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(19) N-[2-(5-bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(20) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(21) N-[3-(4 chlorophenyl)-2-(2-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(22) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(23) N-[3-(4-chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(24) N-[3 (4-chlorophenyl)-2-(5-fluoro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(25) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(26) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(27) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide;
(28) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(29) N-[2-(5-chloro-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-4-pyridyloxy)-2-methylpropanamide;
(30) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(31) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(32) N-[2-(5-cyano-3-pyridyl)-3-(3,4-difluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(33) N-[3-(3-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(34) N-[2-(5-cyano-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(35) N-[2-(5-bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(36) N-[2-(5-bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(37) N-[2 (5 bromo-3-pyridyl)-3-(4-fluorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(38) N-[2 (5 bromo-3-pyridyl)-3-(4-chlorophenyl)-1-methylpropyl]-2-(6-trifluoromethyl-4-pyrimidyloxy)-2-methylpropanamide;
(39) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(40) N-[2 (5-chloro-3-pyridyl)-3-(4-chloro-3-iodophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(41) N-(3-(4 chlorophenyl)-2-benzisoxazol-3-yl)-1-methyl)propyl-2-(5-chloro-2-oxypyridine-2-yl)-2-methylpropanamide;
(42) N-(3-(4 chlorophenyl)-2-(benzisoxazol-3-yl)-1-methyl)propyl-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;
(43) N-(3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl)propyl-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;
(44) N-(3-(4-chlorophenyl)-2-(indol-N-yl)-1-methyl)propyl-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;
(45) N-(3 (4-chlorophenyl)-2-(indolin-N-yl)-1-methyl)propyl-2(4-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;
(46) N-(3-(4-chlorophenyl)-2-(indolin-N-yl)-1-methyl)propyl-2(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;
(47) N-(2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylpropanamide;
(48) N-(2-(1H-1,2,3-benzotriazol-1-yl)-3-(4-chlorophenyl)-1-methylpropyl)-2-methyl-2-(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;
(49) N-(3-(4 chlorophenyl)-1-methyl-2-(1H-indazol-1-yl)propyl)-2-methyl-2-(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;
(50) N-(3-(4-chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylpropanamide;
(51) N-(3-(4-chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-3-yl)propyl)-2-methyl-2-(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;
(52) N-(3-(4-chlorophenyl)-1-methyl-2-(1-methyl-1H-indol-4-yl)propyl)-2-methyl-2(5-trifluoromethylpyridin-2-yl)oxy)-2-methylpropanamide;
(53) N-(3-(4-chlorophenyl)-1-methyl-2-(thiophen-2-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide;
(54) N-(3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide;
(55) N-(3-(4-chlorophenyl)-1-methyl-2-(pyrimidin-5-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide; and
(56) N-(3-(4-chlorophenyl)-1-methyl-2-(pyradizin-3-yl)propyl)-2-methyl-2-(5-chloropyridin-2-yl)oxy)-2-methylprpoanamide;
and pharmaceutically acceptable salts thereof.
5. The compound according to claim 3 , selected from:
(1) N-[3 (4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide;
(2) N-[3 (4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-methyl-2-(2-pyridyloxy)propanamide; and
(3) N-(2-(1-(1,2,4-triazolyl))-3-(4-chlorophenyl)-1-methylpropyl)-2-(2-pyridyloxy)-2-methylpropanamide;
and pharmaceutically acceptable salts thereof.
6. The compound according to claim 1 , wherein:
R 1 is selected from:
(1) pyrrolidinyl,
(2) pyridyl, and
(3) triazolyl,
wherein each pyridyl is optionally substituted with one or two substituents selected from halogen, methyl, trifluoromethyl, cyano and methoxy, and each pyridyl is optionally present as the N-oxide,
R 2 is selected from:
(1) benzyl,
(2) phenylethyl,
(3) 3-phenylpropyl, and
(4) 2-phenylpropyl,
wherein each aryl is optionally substituted with one or two R b substituents selected from halogen, trifluoromethyl, cyano, methoxycarbonyl, and methoxy;
R 3 is selected from:
(1) hydrogen,
(2) methyl, and
(3) ethyl;
R 4 is hydrogen;
R 5 is C 1-8 alkyl substituted with —OR d , wherein R d is heteroaryl and wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;
R d is selected from:
(1) hydrogen,
(2) C 1-4 alkyl,
(3) C 2-6 alkenyl,
(4) cycloalkyl,
(5) cycloalkyl-C 1-4 alkyl,
(6) cycloheteroalkyl,
(7) cycloheteroalkyl-C 1-4 alkyl,
(8) phenyl,
(9) heteroaryl,
(10) phenyl-C 1-4 alkyl, and
(11) heteroaryl-C 1-4 alkyl,
wherein each R d may be unsubstituted or substituted with one to three substituents selected from R h ;
each R h is independently selected from:
(1) halogen,
(2) C 1-4 alkyl,
(3) —O—C 1-4 alkyl,
(4) —S—C 1-4 alkyl,
(5) —CN,
(6) —CF 3 , and
(7) —OCF 3 ;
and pharmaceutically acceptable salts thereof.
7. The compound according to claim 3 , wherein:
R 1 is
heteroaryl
wherein heteroaryl is optionally substituted with one to three substituents independently selected from R b ;
R 2 is
(3) aryl-C 1-4 allyl,
wherein each aryl is optionally substituted with one to three substituents independently selected from R b ;
R 3 is methyl;
R 4 is hydrogen;
R 5 is
wherein R d is heteroaryl and wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;
each R b is independently selected from:
(1) halogen,
(2) cyano,
(3) trifluoromethyl,
(4) trifluoromethoxy,
(5) C 1-3 alkyloxy, and
(6) C 1-3 alkyl;
each R c is independently selected from
(1) hydrogen,
(2) methyl, and
(3) trifluoromethyl;
R d is independently selected from:
(1) hydrogen,
(2) C 1-6 alkyl,
(3) cycloalkyl,
(4) aryl,
(5) heteroaryl,
(6) arylmethyl, and
(7) heteroarylmethyl,
each R d may be unsubstituted or substituted with one to three substituents selected from R h ;
each R h is independently selected from:
(1) halogen,
(2) C 1-3 alkyl,
(3) —CN, and
(4) —CF 3 ;
wherein when pyridyl groups are unsubstituted on the nitrogen, they are may optionally be present as the N-oxide;
and pharmaceutically acceptable salts thereof.
8. The compound according to claim 7 , wherein:
R 1 is selected from:
(1) pyridyl,
(2) indolyl,
(3) 7-aza-indolyl, and
(4) thiophenyl;
wherein each heteroaryl is optionally substituted with one or two substitutents independently selected from R b , and each pyridyl may be optionally present as the N-oxide;
R 2 is
phenylmethyl,
wherein each aryl is optionally substituted with one to three substituents independently selected from R b ;
each R b is independently selected from:
(1) halogen,
(2) cyano,
(3) C 1-3 alkyloxy, and
(4) C 1-3 alkyl;
R d is selected from:
(1) pyridyl, and
(2) pyrimidinyl,
wherein R d may be unsubstituted or substituted with one or two substituents selected from R h ;
each R h is independently selected from:
(1) fluoro,
(2) chloro,
(3) methyl,
(4) —CN, and
(5) —CF 3 ;
and pharmaceutically acceptable salts thereof.
9. The compound according to claim 8 , selected from:
(1) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(2) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(3) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(4) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(5) N-[3-(4-chlorophenyl)-1-methyl-2-(thiophen-3-yl)propyl]-2-(5-chloro-2-pyridyloxy)-2-methylpropanamide;
(6) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;
(8) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl)propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(8) N-[3-(4-chloro-phenyl)-2-(1-indolinyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide; and
(9) N-[3-(4-chlorophenyl)-2-(1-oxido-5-cyano-3-pyridyl]-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
and pharmaceutically acceptable salts thereof.
10. The compound according to claim 8 , wherein R d is 5-trifluoromethyl-2-pyridyl; and pharmaceutically acceptable salts thereof.
11. The compound according to claim 10 selected from:
(1) N-[3-(4-chlorophenyl)-2-(3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(2) N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(3) N-[3-(4-chlorophenyl)-2-(5-methyl-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(4) N-[3-(4-chlorophenyl)-2-(5-cyano-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(5) N-[3-(4-chlorophenyl)-2-(1-indolyl)-1-methyl]propyl]-2-(5-trifluoromethyl-2-oxypyridine-2-yl)-2-methylpropanamide;
(6) N-[3-(4-chlorophenyl)-2-(7-azaindol-N-yl)-1-methyl]propyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(7) N-[3-(4-chloro-phenyl)-2-(1-indolinyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
(8) N-[3-(4-chlorophenyl)-2-(1-oxido-5-cyano-3-pyridyl]-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide;
and pharmaceutically acceptable salts thereof.
12. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
13. A compound of structural formula I:
or a pharmaceutically acceptable salt thereof, wherein;
R 1 is selected from:
(1) cycloheteroalkyl, and
(2) heteroaryl,
wherein each is optionally substituted with one to four substituents independently selected from R b ;
R 2 is
aryl-C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a , and each aryl is optionally substituted with one to four substituents independently selected from R b ;
R 3 is selected from:
(1) hydrogen, and
(2) C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a ;
R 4 is selected from:
(1) hydrogen, and
(2) C 1-4 alkyl,
wherein each alkyl is optionally substituted with one to four substituents independently selected from R a ;
R 5 is C 1-8 alkyl substituted with —OR d , wherein R d is heteroaryl and wherein heteroaryl is unsubstituted or substituted with one to three substituents selected from R h ;
each R a is independently selected from:
(1) —OR d ,
(2) —NR c S(O) m R d ,
(3) halogen,
(4) —S(O) m R d ,
(5) —S(O) m NR c R d ,
(6) —NR c R d ,
(7) —C(O)R d ,
(8) —CO 2 R d ,
(9) —CN,
(10) —C(O)NR c R d ,
(11) —NR c C(O)R d ,
(12) —NR c C(O)OR d ,
(13) —NR c C(O)NR c R d ,
(14) —CF 3 ,
(15) —OCF 3 , and
(16) cycloheteroalkyl;
each R b is independently selected from:
(1) halogen,
(2) cyano,
(3) C 1-3 alkyloxy and
(4) C 1-3 alkyl;
each R c is independently selected from:
(1) hydrogen,
(2) methyl, and
(3) trifluoromethyl;
R d is selected from:
(1) phenyl,
(2) pyridyl, and
(3) pyrimidinyl,
wherein R d may be unsubstituted or substituted with one or two substituents selected from R h ;
each R g is independently selected from:
(1) C 1-4 alkyl, and
(2) —C(O)C 1-4 alkyl;
each R h is independently selected from:
(1) halogen,
(2) C 1-3 alkyl,
(3) —CN, and
(4) —CF 3 ;
m is selected from 0, 1 and 2.