MACROCYCLIC COMPOUNDS AS INHIBITORS OF VIRAL REPLICATION
The embodiments provide compounds of the general formulas I-XIX, as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating flaviviral infection, including hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
1 . A compound having the formula:
wherein:
R 4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
R 5 is C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C 1-6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy, or Y is a carboxylic acid;
V is selected from OH, SH, or NH 2 ;
the dashed line represents an optional double bond;
R 21 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 21 is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R 22 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
2 . The compound of claim 1 of the formula:
3 . The compound of claim 2 , wherein Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy, and wherein V is selected from OH and NH 2 .
4 . A compound having the formula:
wherein:
R 4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
R 5 is C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 ;
R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C 1-6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is COOR 9 , wherein R 9 is C 1-6 alkyl; or Y is a carboxylic acid;
V is selected from OH, SH, or NH 2 ;
the dashed line represents an optional double bond;
R 21 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 21 is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R 22 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
5 . The compound of claim 4 , wherein:
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is a carboxylic acid.
6 . The compound of claim 4 , wherein:
C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .
7 . The compound of claim 5 , wherein:
R 4 is H;
R 5 is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ; and
V is selected from OH and NH 2 .
8 . The compound of claim 7 , wherein:
R 5 is C(O)OR 8 ; and
R 8 is C 1-6 alkyl.
9 . The compound of claim 4 , wherein:
R 4 is H;
R 5 is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ; and
V is selected from OH and NH 2 .
10 . The compound of claim 9 , wherein:
R 5 is C(O)OR 8 ;
R 8 is C 1-6 alkyl;
Y is COOR 9 ;
R 9 is C 1-6 alkyl;
the dashed line is a double bond; and
V is OH.
11 . A compound having the formula:
wherein:
R 4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
R 5 is C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 ;
R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C 1-6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is COOR 9 , wherein R 9 is C 1-6 alkyl; or Y is a carboxylic acid;
V is selected from OH, SH, or NH 2 ;
R 21 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 21 is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R 22 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
12 . The compound of claim 11 , wherein:
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is a carboxylic acid.
13 . The compound of claim 11 , wherein:
C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .
14 . The compound of claim 11 , wherein:
R 4 is H;
R 5 is C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ; and
V is selected from OH and NH 2 .
15 . The compound of claim 14 , wherein:
R 5 is C(O)OR 8 ; and
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy.
16 . The compound of claim 15 , wherein:
R 8 is C 1-6 alkyl; and
V is OH.
17 . The compound of claim 14 , wherein:
R 5 is C(O)OR 8 ; and
Y is COOR 9 , wherein R 9 is C 1-6 alkyl.
18 . The compound of claim 17 , wherein:
R 8 is C 1-6 alkyl; and
V is OH.
19 . A method of making a compound, comprising:
performing an olefin metathesis ring forming reaction with a compound of formula:
to provide a compound of formula:
wherein:
R 4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
R 5 is C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 ;
R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C 1-6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is COOR 9 , wherein R 9 is C 1-6 alkyl; or Y is a carboxylic acid;
V is selected from OH, SH, or NH 2 ;
R 21 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 21 is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R 22 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
20 . The compound of claim 19 , wherein:
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is a carboxylic acid.
21 . The compound of claim 19 , wherein:
C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .
22 . The method of claim 19 , wherein:
R 4 =H;
R 5 is C(O)OR 8 ;
R 8 is C 1-6 alkyl; and
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 where R 9 is C 1-3 alkyl or C 3-7 cycloalkyl; or Y is COOR 9 , where R 9 is C 1-6 alkyl.
23 . The method of claim 22 , wherein:
Y is COOR 9 , where R 9 is C 1-6 alkyl.
24 . The method of claim 19 , further comprising:
performing a coupling reaction to provide the compound of formula:
wherein:
Q is the core ring
wherein the core ring is unsubstituted or substituted with halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, substituted C 1-6 alkyl, substituted C 1-6 alkoxy, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl; and
W is O, S or NH.
25 . The method of claim 24 , wherein the coupling reaction employs:
carbonyldimidazole and an amine,
wherein the amine has the formula
and is unsubstituted or substituted with halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, substituted C 1-6 alkyl, substituted C 1-6 alkoxy, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl.
26 . The method of claim 24 wherein the coupling reaction employs a coupling agent having the formula:
wherein the coupling agent is unsubstituted or substituted with halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, substituted C 1-6 alkyl, substituted C 1-6 alkoxy, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl.
27 . The method of claim 26 , wherein the coupling agent is substituted with a halo.
28 . The method of claim 27 , wherein the halo is fluoro.
29 . A method of preparing a compound having the formula:
comprising
performing an olefin metathesis ring forming reaction with the compound of formula:
wherein:
R 4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, or benzyl, said phenyl or benzyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
R 5 is C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 ;
R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 8 is C 1-6 alkyl optionally substituted with up to 5 fluoro groups; or R 8 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyran ring linked through the C 4 position of the tetrahydropyran ring;
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is COOR 9 , wherein R 9 is C 1-6 alkyl; or Y is a carboxylic acid;
V is selected from OH, SH, or NH 2 ;
R 21 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl; or R 21 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 21 is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R 22 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
30 . The compound of claim 29 , wherein:
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-3 alkyl, C 3-7 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-3 alkyl, C 3-7 cycloalkyl, or C 1-3 alkoxy; or Y is a carboxylic acid.
31 . The compound of claim 29 , wherein:
C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , S(O) 2 R 8 , or (CO)CHR 22 NH(CO)R 21 .
32 . The method of claim 29 , wherein:
R 4 =H;
R 5 is C(O)OR 8 ;
R 8 is C 1-6 alkyl; and
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 where R 9 is C 1-3 alkyl or C 3-7 cycloalkyl; or Y is COOR 9 , where R 9 is C 1-6 alkyl.
33 . The method of claim 32 , wherein:
Y is COOR 9 , where R 9 is C 1-6 alkyl.