US2009286843A1PendingUtilityA1
Macrocyclic compounds as inhibitors of viral replication
Est. expiryOct 14, 2023(expired)· nominal 20-yr term from priority
Inventors:Lawrence M. BlattSteven W. AndrewsKevin Ronald CondroskiGeorge A. DohertyYutong JiangJohn A. JoseyApril L. KennedyMachender R. MadduruPeter J. StengelSteven Mark WenglowskyBenjamin T. WoodardLaura Woodard
C07K 5/0804A61P 31/12
67
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
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.
Claims
exact text as granted — not AI-modified1 . A compound having the Formula I:
wherein:
Q is a core ring selected from
wherein the core ring can be 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, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl,
or Q is R 1 -R 2 , wherein R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 6 R 7 , 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; and R 2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 6 R 7 , 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 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, 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;
R 5 is H, 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, 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 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 1-6 alkyl, C 3-7 cycloalkyl, or 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 9 is NR 1a R 1b , or R 9 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 9 is a C 1-6 alkyl optionally substituted with up to 5 fluoro groups, NR 6 R 7 , NR 1a R 1b , or (CO)OH, or R 9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C 1-6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
wherein R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl,
or R 1a and R 1b are each independently H and 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 1a and R 1b are each independently H, heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl,
or NR 1a R 1b is a heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl,
or R 1c is NH(CO)OR 1e , wherein R 1e is C 1-6 alkyl or C 3-6 cycloalkyl;
p=0 or 1;
V is selected from O, S, or NH;
when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 15 , where R 15 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro;
the dashed lines represent 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, or 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, or 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 , wherein the core ring is
3 . The compound of claim 1 , wherein the core ring is
4 . The compound of claim 1 , wherein the core ring is
5 . The compound of claim 1 of the formula Ia:
6 . The compound of claim 1 of the formula Ib
7 . The compound of claim 1 of the formula Ic:
8 . The compound of claim 1 of the formula Id:
9 . The compound of claim 1 of the formula Ie:
10 . The compound of claim 1 of the formula If:
11 . The compound of claim 1 of the formula Ig:
12 . The compound of claim 1 of the formula Ih:
13 . The compound of claim 1 of the formula Ii:
14 . The compound of claim 1 of the formula Ij:
15 . The compound of claim 1 of the formula Iz:
16 . The compound of claim 1 , wherein Y is sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, and NR 1a R 1b , wherein R 1a and R 1b are each independently H, C 1-6 alkyl, or C 3-7 cycloalkyl.
17 . The compound of claim 2 , wherein Y is sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, and NR 1a R 1b , wherein R 1a and R 1b are each independently H, C 1-6 alkyl, or C 3-7 cycloalkyl.
18 . The compound of claim 3 , wherein Y is sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, and NR 1a R 1b , wherein R 1a and R 1b are each independently H, C 1-6 alkyl, or C 3-7 cycloalkyl.
19 . The compound of claim 4 , wherein Y is sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, and NR 1a R 1b , wherein R 1a and R 1b are each independently H, C 1-6 alkyl, or C 3-7 cycloalkyl.
20 . The compound of claim 1 , wherein the C13-C14 double bond is cis.
21 . The compound of claim 1 , wherein the C13-C14 double bond is trans.
22 . A pharmaceutical composition comprising:
a) the compound of claim 1 ; and b) a pharmaceutically acceptable carrier.
23 . The pharmaceutical composition of claim 22 in a formulation free of any alcohol and any poly-ol.
24 . The pharmaceutical composition of claim 23 , wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).
25 . The pharmaceutical composition of claim 22 in a tablet formulation.
26 . The pharmaceutical composition of claim 22 in a caplet formulation.
27 . The pharmaceutical composition of claim 22 in a capsule formulation.
28 - 67 . (canceled)
68 . A compound having the Formula II, III, or IV:
wherein:
(a) R 1 and R 2 are each independently H, 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 . C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O)R 8 , NHC(O)OR 8 , SO m R 8 , NHS(O) 2 R 8 , (CH 2 ) n NR 6 R 7 , O(CH 2 ) n NR 6 R 7 , or O(CH 2 ) n R 16 where R 16 is imidazolyl or pyrazolyl; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R 1 and R 2 are optionally substituted by up to two 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; said C 6 or 10 aryl, pyridyl, phenoxy and thiophenoxy in the definition of R 1 and R 2 are 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;
(b) m=0, 1, or 2;
(c) 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;
(d) R 5 is H, 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 ;
(e) 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, hydroxy-C 1-6 alkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro, 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;
(f) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, or 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, 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;
(g) Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-6 alkyl, C 3-7 cycloalkyl, or 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 9 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 9 is a C 1-6 alkyl optionally substituted with up to 5 fluoro groups, NR 6 R 7 , or (CO)OH, or R 9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C 1-6 alkoxy; or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof,
(h) R 10 and R 11 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or 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 14 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; said C 6 or 10 aryl, in the definition of R 10 and R 11 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 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 10 and R 11 are combined as O;
(i) p=0 or 1;
(j) R 12 and R 13 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 4 where R 4 is H, 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 14 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; said C 6 or 10 aryl, in the definition of R 12 and R 13 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 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 12 and R 13 are each independently C 1-6 alkyl optionally substituted with (CH 2 ) n OR 8 ;
(k) R 20 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, 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 14 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; said C 6 or 10 aryl, in the definition of R 12 and R 1 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro;
(l) n=1-4;
(m) V is selected from O, S, or NH;
(n) when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 5 , where R 15 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro;
(O) the dashed line represents an optional double bond;
(p) 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, 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 21 is pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
(q) 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; and
(r) Z is a fused or appended aryl or heteroaryl ring system.
69 . A compound having the Formula XI:
wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H and 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 1a and R 1b are each independently H or heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or NR 1a R 1b is a heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or R 1c is NH(CO)OR 1e wherein R 1e is C 1-6 alkyl, or C 3-6 cycloalkyl;
(b) W is O or NH;
(c) V is selected from O, S, or NH;
(d) when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 5 , where R 15 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro;
(e) R 2 is a bicyclic secondary amine with the structure of:
wherein R 21 and R 22 are each independently H, 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, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O)R 8 , NHC(O)OR 8 , SOmR 8 (m=0, 1 or 2), or NHS(O) 2 R 8 ; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of
R 21 and R 22 are optionally substituted by up to two 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; said C 6 or 10 aryl, pyridyl, phenoxy and thiophenoxy in the definition of R 21 and R 22 are 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;
wherein R 10 and R 11 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or 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 14 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; said C 6 or 10 aryl, in the definition of R 12 and R 13 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 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 10 and R 11 are combined as O;
wherein p=0 or 1;
wherein R 12 and R 13 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or 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 14 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; said C 6 or 10 aryl, in the definition of R 12 and R 13 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 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
wherein R 20 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or 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 14 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; said C 6 or 10 aryl, in the definition of R 12 and R 13 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;
wherein n=0-4;
wherein 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, 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 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
or R 2 is R 2a -R 2b when W=NH and V=O, wherein 2a
R 2a is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 2c R 2d , 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 2b is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 2c R 2d , 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;
said R 2c and R 2d 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, 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 2c and R 2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) R 4 is 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, 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;
(g) R 5 is H, C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6l R 7 , C(O)R 8 , C(O)OR 8 , or S(O) 2 R 8 ;
(h) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, or 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; and
(i) the dashed line represents an optional double bond.
70 . A compound having the Formula XVIII:
wherein
(a) R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 5 R 6 , 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;
(b) R 2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole, each optionally substituted with up to three NR 5 R 6 , 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;
(c) R 3 is 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, 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;
(d) R 4 is C 1-6 alkyl, C(O)NR 5 R 6 , C(S)NR 5 R 6 , C(O)R 7 , C(O)OR 7 or S(O) 2 R 7 ;
(e) R 5 and R 6 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, hydroxy-C 1-6 alkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 5 and R 5 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
(f) R 7 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 7 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;
(g) R 8 is C 1-3 alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy; and
(h) the dashed line represents an optional double bond;
or a pharmaceutically acceptable salt thereof.
71 . A compound having the formula:
wherein:
Q is a core ring selected from:
wherein the core ring can be 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, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, 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, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl,
or Q is R 1 —R 2 , wherein R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 - alkylcycloalkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 6 R 7 , 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; and R 2 is H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, benzimidazole, each optionally substituted with up to three NR 6 R 7 , 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 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, 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 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 COOR 9 , wherein R 9 is C 1-6 alkyl;
V is selected from O, S, or NH;
when V is O or S, W is selected from O, NR 15 , or CR 15 ; when V is NH, W is selected from NR 15 or CR 5 , where R 15 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl or C 1-6 alkyl optionally substituted with up to 5 fluoro;
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, or 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, or 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.
72 . The compound of claim 71 of the formula Iz:
73 . The compound of claim 68 represented by Formula (II), wherein:
R 1 is H, 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 2 is H, O(CH 2 ) n NR 6 R 7 , O(CH 2 ) n R 16 , 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; said R 6 and R 7 in the definition of R 2 being each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl; or said R 6 and R 7 in the definition of R 2 taken together with the nitrogen to which they are attached form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; n=1-3; R 4 =H; R 5 is H, C(O)NR 6 R 7 or C(O)OR 8 , said R 6 and R 7 in the definition of R 5 being each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl; R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; 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 tetrahydropyranyl ring linked through the C 4 position of the tetrahydropyranyl ring; Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , where R 9 is C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, all of which are optionally substituted from one to three times with halo, C 1-6 alkoxy, or phenyl; R 10 , R 11 , R 12 and R 13 are H; p=0 or 1; V=O; and W is selected from O, NH, or CH 2 .
74 . The compound of claim 68 in which p=0.
75 . The compound of claim 68 in which p=1.
76 . The compound of claim 68 in which either or both of R 1 and R 2 are H.
77 . The compound of claim 76 in which p=0.
78 . The compound of claim 76 in which p=1.
79 . The compound of claim 68 in which neither R 1 nor R 2 is H.
80 . The compound of claim 79 in which p=0.
81 . The compound of claim 79 in which p=1.
82 . The compound of claim 68 in which R 2 is O(CH 2 ) n NR 6 R 7 or O(CH 2 ) n R 16 .
83 . The compound of claim 68 in which R 9 is C 1-6 alkyl, C 3-7 cycloalkyl, or 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.
84 . The compound of claim 68 in which R 9 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.
85 . The compound of claim 68 in which R 9 is a heteroaromatic ring optionally substituted up to two times with halo, cyano, nitro, hydroxyl, or C 1-6 alkoxy.
86 . The compound of claim 68 in which R 9 is a C 1-6 alkyl optionally substituted with up to 5 fluoro groups, NR 6 R 7 , or (CO)OH.
87 . The compound of claim 68 in which the dashed line in Formula (II), (III), or (IV) represents a single bond.
88 . The compound of claim 68 compound having the Formula V:
wherein:
(a) R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(b) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(c) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl;
(d) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or 3-tetrahydrofuryl;
(e) 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 or pharmaceutically acceptable salt, solvate, or prodrug thereof;
(f) R 10 and R 11 are each independently H, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
(g) W is selected from O or NH; and
(h) the dashed line represents an optional double bond.
89 . The compound of claim 68 having the general Formula VI:
wherein:
(a) R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(b) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , C(O)OR 8 ;
(c) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or 3-tetrahydrofuryl;
(d) 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 or pharmaceutically acceptable salt, solvate, or prodrug thereof,
(e) W is selected from O or NH; and
(f) the dashed line represents an optional double bond.
90 . A compound having the general Formula VII:
wherein:
(a) R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy;
(b) R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
(c) R 8 is C 1-6 alkyl, C 5-6 cycloalkyl, or 3-tetrahydrofuryl;
(d) R 9 is C 1-3 alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy;
(e) R 10 and R 11 are each independently H, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
(f) W is selected from O or NH; and
(g) the dashed line represents an optional double bond.
91 . A compound having the general Formula VIII:
wherein:
(a) R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(b) R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
(c) R 8 is C 1-6 alkyl, C 5-6 cycloalkyl, or 3-tetrahydrofuryl;
(d) R 9 is C 1-3 alkyl, C 3-5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(e) R 10 and R 11 are each independently H, C 1-3 alkyl, or C 4-5 cycloalkyl;
(f) W is selected from O or NH; and
(g) the dashed line represents an optional double bond.
92 . The compound of claim 68 having the general Formula IX:
wherein:
(a) R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(b) R 5 is H, C(O)OR 8 or C(O)NHR 6 ;
(c) R 6 is C 1-6 alkyl or C 5-6 cycloalkyl;
(d) R 8 is C 1-6 alkyl or C 5-6 cycloalkyl;
(e) R 9 is C 1-3 alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(f) R 10 and R 11 are each independently H, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl or cyclobutyl;
(g) the dashed line represents an optional double bond.
93 . The compound of claim 68 having the general Formula X:
wherein:
(a) R 1 and R 2 are each independently H, chloro, fluoro, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(b) R 5 is H, C(O)OR 8 or C(O)NHR;
(c) R 6 is C 1-6 alkyl or C 5-6 cycloalkyl;
(d) R 8 is C 1-6 alkyl or C 5-6 cycloalkyl;
(e) R 9 is C 1-3 alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy; and
(f) the dashed line represents an optional double bond.
94 . A pharmaceutical composition comprising:
a) the compound of claim 68 ; and b) a pharmaceutically acceptable carrier.
95 . The pharmaceutical composition of claim 94 in a formulation free of any alcohol and any poly-ol.
96 . The pharmaceutical composition of claim 95 , wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).
97 . The pharmaceutical composition of claim 94 in a tablet formulation.
98 . The pharmaceutical composition of claim 94 in a caplet formulation.
99 . The pharmaceutical composition of claim 94 in a capsule formulation.
100 - 139 . (canceled)
140 . A compound having the Formula XII:
wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H or heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
(b) R 21 and R 22 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(c) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(d) R 67 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl;
(e) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or 3-tetrahydrofuryl;
(f) R 10 and R 11 are each independently H, halo, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
(g) R 12 and R 13 are each independently H, halo, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, or C 1-6 alkyl optionally substituted with up to 5 halo atoms; and
(h) the dashed line represents an optional double bond.
141 . A compound having the Formula XIII:
wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H or heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
(b) R 21 and R 22 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(c) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(d) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl;
(e) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or 3-tetrahydrofuryl; and
(f) the dashed line represents an optional double bond.
142 . A compound having the Formula XIV:
wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H or heteroaryl selected from a group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
(b) R 2a is C 6 or C 10 aryl optionally substituted with up to three NR 2c R 2d , 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro;
said R 2c and R 2d 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, 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 2c and R 2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
or R 2a is an unsaturated five- or six-membered heteroaryl, or such defined heteroaryl fused to another cycle be it heterocycle or any other cycle;
(c) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(d) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl;
(e) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or 3-tetrahydrofuryl; and
(f) the dashed line represents an optional double bond.
143 . A pharmaceutical composition comprising:
a) the compound of claim 69 ; and b) a pharmaceutically acceptable carrier.
144 . The pharmaceutical composition of claim 143 in a formulation free of any alcohol and any poly-ol.
145 . The pharmaceutical composition of claim 144 , wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).
146 . The pharmaceutical composition of claim 143 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.
147 . The pharmaceutical composition of claim 143 in a tablet formulation.
148 . The pharmaceutical composition of claim 143 in a caplet formulation.
149 . The pharmaceutical composition of claim 143 in a capsule formulation.
150 - 189 . (canceled)
190 . The compound of claim 70 , wherein
R 1 is phenyl, benzothiazole, benzothiophene, benzofuran, or benzimidazole, each optionally substituted with up to 1-2 NR 5 R 6 , halo, cyano, nitro, hydroxy, C 1-2 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, 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 2 is H, phenyl, pyridine, pyrimidine, thiazole, oxazole, isoxazole, or pyrazole, each optionally substituted with up to 1-2 NR 5 R 6 , 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 3 is H; R 5 is C 1-6 alkyl, C(O)NR 5 R 6 , C(S)NR 5 R 6 , C(O)R 7 , C(O)OR 7 , or S(O) 2 R 7 ; R 5 and R 6 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 two halo, cyano, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, or 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 5 and R 6 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl; R 7 is C 1-6 alkyl, C 3-7 cycloalkyl, or 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 7 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; R 8 is C 1-3 alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy; and the dashed line represents an optional double bond.
191 . The compound of claim 70 , wherein
R 1 is phenyl, benzothiazole, or benzothiophene each optionally substituted with up to 1-2 halo, hydroxy, C 1-2 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 2 is H or phenyl optionally substituted with up to 1-2 halo, hydroxy, C 1-3 alkyl, alkyl, or C 1-3 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; R 3 is H; R 4 is C 1-6 alkyl, C(O)NR 5 R 6 , C(O)R 7 , or C(O)OR 7 ; R 5 is H and R 6 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl, said phenyl optionally substituted by up to two halo, cyano, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; R 7 is C 1-6 alkyl or C 3-7 cycloalkyl, which are all optionally substituted from one to three times with halo or phenyl; or R 7 is C 6 or 10 aryl which is optionally substituted by up to one 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; R 8 is C 1-3 alkyl, C 3-4 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy; and the dashed line represents an optional double bond.
192 . A pharmaceutical composition comprising:
a) the compound of claim 70 ; and b) a pharmaceutically acceptable carrier.
193 . The pharmaceutical composition of claim 192 in a formulation free of any alcohol and any poly-ol.
194 . The pharmaceutical composition of claim 193 , wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).
195 . The pharmaceutical composition of claim 192 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.
196 . The pharmaceutical composition of claim 192 in a tablet formulation.
197 . The pharmaceutical composition of claim 192 in a caplet formulation.
198 . The pharmaceutical composition of claim 192 in a capsule formulation.
199 - 238 . (canceled)
239 . The compound of claim 1 having the formula:
240 . A compound having the Formula XII:
wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H or heteroaryl selected from the group consisting of:
wherein R″C is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
(b) R 21 and R 22 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(c) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(d) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl;
(e) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or 3-tetrahydrofuryl;
(f) R 10 and R 11 are each independently H, halo, C 1-3 alkyl, or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
(g) R 12 and R 13 are each independently H, halo, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, or C 1-6 alkyl optionally substituted with up to 5 halo atoms; and
(h) the dashed line represents an optional double bond.
241 . A compound having the Formula XIII:
wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H or heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
(b) R 21 and R 22 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(c) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(d) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl;
(e) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 - alkylcycloalkyl, or 3-tetrahydrofuryl; and
(f) the dashed line represents an optional double bond.
242 . A compound having the Formula XIV:
wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 alkylcycloalkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H or heteroaryl selected from a group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or NR 1a R 1b is a three- to six- membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
(b) R 2a is C 6 or C 10 aryl optionally substituted with up to three NR 2c R 2d , 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, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro;
said R 2c and R 2d 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, 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 2c and R 2d are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
or R 2a is an unsaturated five- or six-membered heteroaryl, or such defined heteroaryl fused to another cycle be it heterocycle or any other cycle;
(c) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(d) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 alkylcycloalkyl, or phenyl;
(e) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 - alkylcycloalkyl, or 3-tetrahydrofuryl; and
(f) the dashed line represents an optional double bond.
243 . A pharmaceutical composition comprising:
a) a compound having the formula:
or a pharmaceutically acceptable salt thereof; and
b) a pharmaceutically acceptable carrier.
244 . The pharmaceutical composition of claim 243 in a formulation free of any alcohol and any poly-ol.
245 . The pharmaceutical composition of claim 244 , wherein the formulation is free of any sugar alcohol and any poly (ethylene glycol) (PEG).
246 . The pharmaceutical composition of claim 243 in an aqueous formulation free of any excipient that reduces polarity in the aqueous formulation.
247 . The pharmaceutical composition of claim 243 in a tablet formulation.
248 . The pharmaceutical composition of claim 243 in a caplet formulation.
249 . The pharmaceutical composition of claim 243 in a capsule formulation.
250 - 289 . (canceled)Join the waitlist — get patent alerts
Track US2009286843A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.