US2005113578A1PendingUtilityA1
Process for preparing substituted pyridines
Est. expiryMar 31, 2020(expired)· nominal 20-yr term from priority
A61P 3/10C07F 7/1892C07F 7/188C07F 7/1804Y02P20/55C07D 213/38
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Claims
Abstract
A process for preparing a compound of the formula wherein n, R 1 , R 2 , R 3 and X are as defined above, used as an intermediate in the synthesis of β-adrenergic receptor agonists.
Claims
exact text as granted — not AI-modified1 - 17 . (canceled)
18 . A process for preparing a compound of the formula
wherein n is 0, 1, 2 or 3;
each R 2 is independently hydrogen, halo, trifluoromethyl, cyano, SR 4 , OR 4 , SO 2 R 4 , OCOR 5 , or (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R 4 ) 2 , SR 4 , trifluoromethyl, OR 4 , (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, NR 4 COR 5 , COR 5 , SO 2 R 5 , OCOR 5 , NR 4 SO 2 R 5 and NR 4 CO 2 R 4 ;
R 4 and R 5 , for each occurrence, are each independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl or (C 1 -C 6 )aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C 1 -C 10 )alkyl-CO 2 , (C 1 -C 10 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, or (C 1 -C 6 )alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C 1 -C 6 )alkyl) 2 amino, pyrrolidine, piperidine, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio and (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C 1 -C 6 )alkyl-CO 2 , (C 1 -C 6 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl and (C 1 -C 6 )alkoxy;
or R 5 is N(R 4 ) 2 wherein R 4 is as defined above;
R 6 is COR 7 or CO 2 R 7 wherein R 7 is (C 1 -C 8 )alkyl; and
Y is
wherein:
Q 1 is oxygen, nitrogen or sulfur;
Q 2 is carbon or nitrogen;
Q 3 is hydrogen, —(CH 2 ) q -phenyl, —(C 1 -C 10 )alkyl, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , or a heterocycle selected from the group consisting of —(CH 2 ) q -pyridyl, —(CH 2 ) q -pyrimidyl, —(CH 2 ) q -pyraziqyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -thiazolyl, —(CH 2 ) q -(1,2,4-oxadiazolyl), —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms, nitro, cyano, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl and —(CH 2 ) q —SO 2 NG 1 G 2 ;
wherein the phenyl moiety of said —(CH 2 ) q -phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C 1 -C 6 )alkoxy optionally independently substituted with one or more halo atoms, (C 1 -C 6 )alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 ; —(CH 2 ) q —NG 3 -SO 2 -G 3 and —(CH 2 ) q —NG 3 -SO 2 —NG 1 G 2 ;
Q 4 is —(CH 2 ) q —CN, —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , —(CH 2 ) q CH 2 OH, (CH 2 ) q —CHO, —(CH 2 ) q —CO-G 3 , —(CH 2 ) q —CONG 1 G 2 , or a heterocycle selected from —(CH 2 ) q -thiazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl, —(CH 2 ) q -1,2,4-oxadiazolyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -tetrazolyl and —(CH 2 ) q -pyrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , halo, nitro, cyano, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, or —(CH 2 ) q —SO 2 NG 1 G 2 ;
Q 5 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 6 is a covalent bond, oxygen or sulfur;
Q 7 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 8 and Q 9 are independently a covalent bond, oxygen, sulfur, NH or N—(C 1 -C 6 )alkyl;
Q 10 is nitro, amino, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (CH 2 ) p OR 11 , (CH 2 ) q CO 2 H, (CH 2 ) q COR 13 , (CH 2 ) q SO 2 NR 11 R 12 , (CH 2 ) q —NR 11 SO 2 R 10 , (CH 2 ) q P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p CO 2 H, (CH 2 ) q —O—(CH 2 ) p COR 13 , (CH 2 ) q —O—(CH 2 ) p P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p SO 2 NR 11 R 12 , or (CH 2 ) q —O—(CH 2 ) p —NR 11 SO 2 R 10 ;
R 8 and R 9 are each independently hydrogen or (C 1 -C 6 )alkyl; and
wherein G 1 and G 2 for each occurrence are each independently hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo, (C 1 -C 8 )alkoxy(C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl, or G 1 and G 2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
G 3 for each occurrence is independently hydrogen or (C 1 -C 6 )alkyl;
R 10 for each occurrence is independently (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 11 and R 12 are taken separately and, for each occurrence, are independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or
R 11 and R 12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy;
R 13 for each occurrence is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, NR 11 R 12 , (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl wherein R 11 and R 12 are as defined above;
R 14 and R 15 are each independently hydrogen, halo, (C 1 -C 6 )alkyl, nitro, cyano, trifluoromethyl, SO 2 R 10 , SO 2 NR 11 R 12 , NR 11 R 12 , COR 13 , CO 2 R 11 , (C 1 -C 6 )alkoxy, NR 11 SO 2 R 10 , NR 11 COR 13 , NR 11 CO 2 R 11 or OR 11 ;
p for each occurrence is independently an integer of 1 to 6; and
q for each occurrence is independently 0 or an integer of 1 to 6;
with the proviso that when Q 9 is O or S then n is not 0;
with the proviso that when Q 1 is oxygen or sulfur then Q 3 is absent; and
with the proviso that when Q 2 is nitrogen then Q 5 is absent;
comprising reacting a compound of the formula
wherein n, R 2 , R 6 and Y are as defined above; and R 3 is tetrahydrofuranyl, tetrahydropyranyl or a silyl protecting group; with tetra-n-butylammonium fluoride.
19 . A process according to claim 18 , wherein the compound of the formula
wherein n, R 2 , R 3 , R 6 and Y are as defined above, is formed by treating a compound of the formula
wherein R 1 is halo and wherein n, R 2 , R 3 , R 6 and Y are as defined above, with ammonium formate in the presence of palladium on carbon.
20 . A process according to claim 19 , wherein the compound of the formula
is formed by reacting the compound
wherein R 1 is hydrogen or halo and wherein n, R 2 , R 3 and Y are as defined above with an organic acid anhydride, a dicarbonate or an organic acid chloride.
21 . A process according to claim 20 , wherein the dicarbonate is di-tert-butyl dicarbonate
22 . A process according to claim 20 , wherein the compound
is formed by reacting the compound
wherein n, R 1 , R 2 , R 3 and X are as defined above, with an amine of the formula H 2 NY, wherein Y is as defined above, in the presence of N,N-diisopropylethylamine.
23 . A process for preparing a compound of the formula
wherein n is 0, 1, 2 or 3;
each R 2 is independently hydrogen, halo, trifluoromethyl, cyano, SR 4 , OR 4 , SO 2 R 4 , OCOR 5 , or (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R 4 ) 2 , SR 4 , trifluoromethyl, OR 4 , (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, NR 4 COR 5 , COR 5 , SO 2 R 5 , OCOR 5 , NR 4 SO 2 R 5 and NR 4 CO 2 R 4 ;
R 4 and R 5 , for each occurrence, are each independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl or (C 1 -C 6 )aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C 1 -C 10 )alkyl-CO 2 , (C 1 -C 10 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, or (C 1 -C 6 )alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C 1 -C 6 )alkyl) 2 amino, pyrrolidine, piperidine, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio and (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C 1 -C 6 )alkyl-CO 2 , (C 1 -C 6 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl and (C 1 -C 6 )alkoxy;
or R 5 is N(R 4 ) 2 wherein R 4 is as defined above;
R 6 is COR 7 or CO 2 R 7 wherein R 7 is (C 1 -C 8 )alkyl; and
Y is
wherein:
Q 1 is oxygen, nitrogen or sulfur;
Q 2 is carbon or nitrogen;
Q 3 is hydrogen, —(CH 2 ) q -phenyl, —(C 1 -C 10 )alkyl, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , or a heterocycle selected from the group consisting of —(CH 2 ) q -pyridyl, —(CH 2 ) q -pyrimidyl, —(CH 2 ) q -pyraziqyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -thiazolyl, —(CH 2 ) q -(1,2,4-oxadiazolyl), —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms, halo, nitro, cyano, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl and —(CH 2 ) q —SO 2 NG 1 G 2 ;
wherein the phenyl moiety of said —(CH 2 ) q -phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C 1 -C 6 )alkoxy optionally independently substituted with one or more halo atoms, (C 1 -C 6 )alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 ; —(CH 2 ) q —NG 3 -SO 2 -G 3 and —(CH 2 ) q —NG 3 -SO 2 —NG 1 G 2 ;
Q 4 is —(CH 2 ) q —CN, —(CH 2 ) q CO 2 G 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , —(CH 2 ) q CH 2 OH, —(CH 2 ) q —CHO, —(CH 2 ) q —CO-G 3 , —(CH 2 ) q —CONG 1 G 2 , or a heterocycle selected from —(CH 2 ) q -thiazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl, —(CH 2 ) q -1,2,4-oxadiazolyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -tetrazolyl and —(CH 2 ) q -pyrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , halo, nitro, cyano, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, or —(CH 2 ) q —SO 2 NG 1 G 2 ;
Q 5 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 6 is a covalent bond, oxygen or sulfur;
Q 7 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 8 and Q 9 are independently a covalent bond, oxygen, sulfur, NH or N—(C 1 -C 6 )alkyl;
Q 10 is nitro, amino, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (CH 2 ) p OR 11 , (CH 2 ) q CO 2 H, (CH 2 ) q COR 13 , (CH 2 ) q SO 2 NR 11 R 12 , (CH 2 ) q —NR 11 SO 2 R 10 , (CH 2 ) q P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p CO 2 H, (CH 2 ) q —O—(CH 2 ) p COR 13 , (CH 2 ) q —O—(CH 2 ) p P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p SO 2 NR 11 R 12 , or (CH 2 ) q —O—(CH 2 ) p —NR 11 SO 2 R 10 ;
R 8 and R 9 are each independently hydrogen or (C 1 -C 6 )alkyl; and
wherein G 1 and G 2 for each occurrence are each independently hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo, (C 1 -C 8 )alkoxy(C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl, or G 1 and G 2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
G 3 for each occurrence is independently hydrogen or (C 1 -C 6 )alkyl;
R 10 for each occurrence is independently (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 11 and R 12 are taken separately and, for each occurrence, are independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or
R 11 and R 12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy;
R 13 for each occurrence is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, NR 1 , R 12 , (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl wherein R 11 and R 12 are as defined above;
R 14 and R 15 are each independently hydrogen, halo, (C 1 -C 6 )alkyl, nitro, cyano, trifluoromethyl, SO 2 R 10 , SO 2 NR 11 R 12 , NR 11 R 12 , COR 13 , CO 2 R 11 , (C 1 -C 6 )alkoxy, NR 11 SO 2 R 10 , NR 11 COR 13 , NR 11 CO 2 R 11 or OR 11 ;
p for each occurrence is independently an integer of 1 to 6; and
q for each occurrence is independently 0 or an integer of 1 to 6;
with the proviso that when Q 9 is O or S then n is not 0;
with the proviso that when Q 1 is oxygen or sulfur then Q 3 is absent; and
with the proviso that when Q 2 is nitrogen then Q 5 is absent;
comprising (a) reacting a compound of the formula
wherein R 1 is hydrogen or halo, and n, R 1 , R 2 , R 3 and X are as defined above), with an amine of the formula H 2 NY, wherein Y is as defined above in the presence of N,N-diisopropylethylamine;
(b) reacting the compound of formula IV so formed
wherein R 1 is hydrogen or halo and wherein n, R 2 , R 3 and Y are as defined above with an organic acid anhydride, a dicarbonate or an organic acid chloride, to form a compound of the formula
(c) treating the compound of formula II, wherein R 1 is halo, so formed in step (b) with ammonium formate in the presence of palladium-on-carbon to form the compound of the formula
wherein n, R 2 , R 3 , R 6 and Y are as defined above, and
(d) treating the compound of formula II so formed with tetra-n-butylammonium fluoride.
24 . A process for preparing a compound of the formula
wherein n is 0, 1, 2 or 3;
each R 2 is independently hydrogen, halo, trifluoromethyl, cyano, SR 4 , OR 4 , SO 2 R 4 , OCOR 5 , or (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R 4 ) 2 , SR 4 , trifluoromethyl, OR 4 , (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, NR 4 COR 5 , COR 5 , SO 2 R 5 , OCOR 5 , NR 4 SO 2 R 5 and NR 4 CO 2 R 4 ;
R 4 and R 5 , for each occurrence, are each independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl or (C 1 -C 6 )aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C 1 -C 10 )alkyl-CO 2 , (C 1 -C 10 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, or (C 1 -C 6 )alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C 1 -C 6 )alkyl) 2 amino, pyrrolidine, piperidine, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio and (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C 1 -C 6 )alkyl-CO 2 , (C 1 -C 6 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl and (C 1 -C 6 )alkoxy;
or R 5 is N(R 4 ) 2 wherein R 4 is as defined above;
R 6 is COR 7 or CO 2 R 7 wherein R 7 is (C 1 -C 8 )alkyl; and
Y is
wherein:
Q 1 is oxygen, nitrogen or sulfur;
Q 2 is carbon or nitrogen;
Q 3 is hydrogen, —(CH 2 ) q -phenyl, —(C 1 -C 10 )alkyl, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , or a heterocycle selected from the group consisting of —(CH 2 ) q -pyridyl, —(CH 2 ) q -pyrimidyl, —(CH 2 ) q -pyraziqyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -thiazolyl, —(CH 2 ) q -(1,2,4-oxadiazolyl), —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms, nitro, cyano, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl and —(CH 2 ) q —SO 2 NG 1 G 2 ;
wherein the phenyl moiety of said —(CH 2 ) q -phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C 1 -C 6 )alkoxy optionally independently substituted with one or more halo atoms, (C 1 -C 6 )alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 ; —(CH 2 ) q —NG 3 -SO 2 -G 3 and —(CH 2 ) q —NG 3 -SO 2 NG 1 G 2 ;
Q 4 is —(CH 2 ) q —CN, —(CH 2 ) q CO 2 G 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , —(CH 2 ) q CH 2 OH, —(CH 2 ) q —CHO, —(CH 2 ) q —CO-G 3 , —(CH 2 ) q —CONG 1 G 2 , or a heterocycle selected from —(CH 2 ) q -thiazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl, —(CH 2 ) q -1,2,4-oxadiazolyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -tetrazolyl and —(CH 2 ) q -pyrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , halo, nitro, cyano, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, or —(CH 2 ) q —SO 2 NG 1 G 2 ;
Q 5 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 6 is a covalent bond, oxygen or sulfur;
Q 7 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 8 and Q 9 are independently a covalent bond, oxygen, sulfur, NH or N—(C 1 -C 6 )alkyl;
Q 10 is nitro, amino, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl. (CH 2 ) p OR 11 , (CH 2 ) q CO 2 H, (CH 2 ) q COR 13 , (CH 2 ) q SO 2 NR 11 R 12 , (CH 2 ) q —NR 11 SO 2 R 10 , (CH 2 ) q P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p CO 2 H, (CH 2 ) q —O—(CH 2 ) p COR 1 3, (CH 2 ) q —O—(CH 2 ) p P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p SO 2 NR 11 , R 12 , or (CH 2 ) q —O—(CH 2 ) p —NR 11 SO 2 R 10 ;
R 8 and R 9 are each independently hydrogen or (C 1 -C 6 )alkyl; and
wherein G 1 and G 2 for each occurrence are each independently hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo, (C 1 -C 8 )alkoxy(C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl, or G 1 and G 2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
G 3 for each occurrence is independently hydrogen or (C 1 -C 6 )alkyl;
R 10 for each occurrence is independently (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 11 and R 12 are taken separately and, for each occurrence, are independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or
R 11 and R 12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy;
R 13 for each occurrence is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, NR 11 R 12 , (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl wherein R 11 and R 12 are as defined above;
R 14 and R 15 are each independently hydrogen, halo, (C 1 -C 6 )alkyl, nitro, cyano, trifluoromethyl, SO 2 R 10 , SO 2 NR 11 R 12 , NR 11 R 12 , COR 13 , CO 2 R 11 , (C 1 -C 6 )alkoxy, NR 11 SO 2 R 10 , NR 11 COR 13 , NR 11 CO 2 R 11 or OR 11 ;
p for each occurrence is independently an integer of 1 to 6; and
q for each occurrence is independently 0 or an integer of 1 to 6;
with the proviso that when Q 9 is O or S then n is not 0;
with the proviso that when Q 1 is oxygen or sulfur then Q 3 is absent; and
with the proviso that when Q 2 is nitrogen then Q 5 is absent;
comprising reacting a compound of the formula
wherein R 1 is halo and wherein n, R 2 , R 3 and Y are as defined above, with ammonium formate in the presence of palladium-on-carbon.
25 . A process according to claim 24 , wherein the compound of the formula
is formed by reacting a compound of the formula
wherein R 1 is hydrogen or halo, and wherein n, R 2 and Y are as defined above, with an organic acid anhydride, a dicarbonate or an organic acid chloride.
26 . A process according to claim 25 , wherein the dicarbonate is di-tert-butyl dicarbonate.
27 . A process according to claim 25 , wherein the compound of the formula
is formed by reacting the compound
wherein n, R 1 , R 2 and X are as defined above, with an amine of the formula H 2 NY, wherein Y is as defined above, in the presence of N,N-diisopropylethylamine.
28 . A process for preparing a compound of the formula
wherein n is 0, 1, 2 or 3;
each R 2 is independently hydrogen, halo, trifluoromethyl, cyano, SR 4 , OR 4 , SO 2 R 4 , OCOR 5 , or (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R 4 ) 2 , SR 4 , trifluoromethyl, OR 4 , (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, NR 4 COR 5 , COR 5 , SO 2 R 5 , OCOR 5 , NR 4 SO 2 R 5 and NR 4 CO 2 R 4 ;
R 4 and R 5 , for each occurrence, are each independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl or (C 1 -C 6 )aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C 1 -C 10 )alkyl-CO 2 , (C 1 -C 10 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, or (C 1 -C 6 )alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C 1 -C 6 )alkyl) 2 amino, pyrrolidine, piperidine, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio and (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C 1 -C 6 )alkyl-CO 2 , (C 1 -C 6 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl and (C 1 -C 6 )alkoxy;
or R 5 is N(R 4 ) 2 wherein R 4 is as defined above;
R 6 is COR 7 or CO 2 R 7 wherein R 7 is (C 1 -C 8 )alkyl; and
Y is
wherein:
Q 1 is oxygen, nitrogen or sulfur;
Q 2 is carbon or nitrogen;
Q 3 is hydrogen, —(CH 2 ) q -phenyl, —(C 1 -C 10 )alkyl, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , or a heterocycle selected from the group consisting of —(CH 2 ) q -pyridyl, —(CH 2 ) q -pyrimidyl, —(CH 2 ) q -pyraziqyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -thiazolyl, —(CH 2 ) q -(1,2,4-oxadiazolyl), —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of (C 1 -C 8 )alkyl optionally independently substituted with one or more halo atoms, nitro, cyano, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl and —(CH 2 ) q —SO 2 NG 1 G 2 ;
wherein the phenyl moiety of said —(CH 2 ) q -phenyl may optionally be substituted with one or more substituents independently selected from the group consisting of (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, hydroxy, (C 1 -C 6 )alkoxy optionally independently substituted with one or more halo atoms, (C 1 -C 6 )alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, —(CH 2 ) q —NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , (CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 ; —(CH 2 ) q —NG 3 -SO 2 -G 3 and —(CH 2 ) q —NG 3 -SO 2 —NG 1 G 2 ;
Q 4 is —(CH 2 ) q —CN, —(CH 2 ) q CO 2 G 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, —(CH 2 ) q —SO 2 NG 1 G 2 , —(CH 2 ) q CH 2 OH, (CH 2 ) q —CHO, —(CH 2 ) q —CO-G 3 , —(CH 2 ) q —CONG 1 G 2 , or a heterocycle selected from —(CH 2 ) q -thiazolyl, —(CH 2 ) q -oxazolyl, —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl, —(CH 2 ) q -1,2,4-oxadiazolyl, —(CH 2 ) q -isoxazolyl, —(CH 2 ) q -tetrazolyl and —(CH 2 ) q -pyrazolyl;
wherein one of the ring nitrogen atoms of said —(CH 2 ) q -imidazolyl, —(CH 2 ) q -triazolyl and —(CH 2 ) q -tetrazolyl may optionally be substituted by (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by one or more substituents independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —CO 2 G 3 , halo, nitro, cyano, —(CH 2 ) q —CO—NG 1 G 2 , —(CH 2 ) q —OG 3 , —(CH 2 ) q —SO 3 G 3 , —(CH 2 ) q —SO 2 —(C 1 -C 6 )alkyl, or —(CH 2 ) q —SO 2 NG 1 G 2 ;
Q 5 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 6 is a covalent bond, oxygen or sulfur;
Q 7 is hydrogen or (C 1 -C 6 )alkyl optionally independently substituted with one or more halo atoms;
Q 8 and Q 9 are independently a covalent bond, oxygen, sulfur, NH or N—(C 1 -C 6 )alkyl;
Q 10 is nitro, amino, (C 2 -C 9 )heteroaryl, (C 2 -C 9 )heterocycloalkyl, (CH 2 ) p OR 11 , (CH 2 ) q CO 2 H, (CH 2 ) q COR 13 , (CH 2 ) q SO 2 NR 11 R 11 R 12 , (CH 2 ) q —NR 11 SO 2 R 10 , (CH 2 ) q P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p CO 2 H, (CH 2 ) q —O—(CH 2 ) p COR 13 , (CH 2 ) q —O—(CH 2 ) p P(O)(OR 8 )(OR 9 ), (CH 2 ) q —O—(CH 2 ) p SO 2 N R 11 R 12 , or (CH 2 ) q —O—(CH 2 ) p —NR 11 SO 2 R 10 ;
R 8 and R 9 are each independently hydrogen or (C 1 -C 6 )alkyl; and
wherein G 1 and G 2 for each occurrence are each independently hydrogen, (C 1 -C 6 )alkyl optionally independently substituted with one or more halo, (C 1 -C 8 )alkoxy(C 1 -C 6 )alkyl or (C 3 -C 8 )cycloalkyl, or G 1 and G 2 together with the nitrogen to which they are attached form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
G 3 for each occurrence is independently hydrogen or (C 1 -C 6 )alkyl;
R 10 for each occurrence is independently (C 1 -C 6 )alkyl or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl;
R 11 and R 12 are taken separately and, for each occurrence, are independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, or
R 11 and R 12 are taken together with the nitrogen atom to which they are attached and form a pyrrolidine, piperidine or morpholine ring wherein said pyrrolidine, piperidine or morpholine may optionally be substituted at any carbon atom by (C 1 -C 4 )alkyl or (C 1 -C 4 )alkoxy;
R 13 for each occurrence is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, NR 11 R 12 , (C 3 -C 8 )cycloalkyl, or (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl wherein R 11 and R 12 are as defined above;
R 14 and R 15 are each independently hydrogen, halo, (C 1 -C 6 )alkyl, nitro, cyano, trifluoromethyl, SO 2 R 11 , SO 2 NR 11 R 12 , NR 11 R 12 , COR 13 , CO 2 R 11 , (C 1 -C 6 )alkoxy, NR 11 SO 2 R 10 , NR 11 COR 13 , NR 11 CO 2 R 11 or OR 11 ;
p for each occurrence is independently an integer of 1 to 6; and
q for each occurrence is independently 0 or an integer of 1 to 6;
with the proviso that when Q 9 is O or S then n is not 0;
with the proviso that when Q 1 is oxygen or sulfur then Q 3 is absent; and
with the proviso that when Q 2 is nitrogen then Q 5 is absent;
comprising (a) reacting the compound of a formula
wherein R 1 is hydrogen or halo, and n, R 1 , R 2 , R 3 and X are as defined above, with an amine of the formula H 2 NY, wherein Y is as defined above, in the presence of N,N-diisopropylethylamine;
(b) reacting the compound of the formula VII so formed
wherein R 1 is hydrogen or halo, and wherein n, R 2 and Y are as defined above with an organic acid anhydride, a dicarbonate or an organic acid chloride to form a compound of the formula
wherein n, R 1 , R 2 , R 6 and Y are as defined above and
(c) reacting the compound of formula VI, wherein R 1 is halo, so formed with ammonium formate in the presence of palladium-on-carbon.
29 . A process for preparing a compound of the formula
wherein n is 0, 1, 2 or 3;
R 1 is hydrogen or halo;
each R 2 is independently hydrogen, halo, trifluoromethyl, cyano, SR 4 , OR 4 , SO 2 R 4 , OCOR 5 , or (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R 4 ) 2 , SR 4 , trifluoromethyl, OR 4 , (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, NR 4 COR 5 , COR 5 , SO 2 R 5 , OCOR 5 , NR 4 SO 2 R 5 and NR 4 CO 2 R 4 ;
R 4 and R 5 , for each occurrence, are each independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl or (C 1 -C 6 )aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C 1 -C 10 )alkyl-CO 2 , (C 1 -C 10 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, or (C 1 -C 6 )alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C 1 -C 6 )alkyl) 2 amino, pyrrolidine, piperidine, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio and (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C 1 -C 6 )alkyl-CO 2 , (C 1 -C 6 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl and (C 1 -C 6 )alkoxy;
or R 5 is N(R 4 ) 2 wherein R 4 is as defined above;
comprising reacting the compound of the formula
wherein n, R 1 , R 2 and X are as defined above, with a non-nucleophilic base.
30 . A process according to claim 29 , wherein the non-nucleophilic base is sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide or 1,8-diazabicyclo[5.4.0]undec-7-ene.
31 - 33 . (canceled)
34 . A compound of the formula
wherein n is 0, 1, 2 or 3;
R 1 is hydrogen or halo;
each R 2 is independently hydrogen, halo, trifluoromethyl, cyano, SR 4 , OR 4 , SO 2 R 4 , OCOR 5 , or (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R 4 ) 2 , SR 4 , trifluoromethyl, OR 4 , (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, NR 4 COR 5 , COR 5 , SO 2 R 5 , OCOR 5 , NR 4 SO 2 R 5 and NR 4 CO 2 R 4 ;
R 4 and R 5 , for each occurrence, are each independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl or (C 1 -C 6 )aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C 1 -C 10 )alkyl-CO 2 , (C 1 -C 10 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, or (C 1 -C 6 )alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C 1 -C 6 )alkyl) 2 amino, pyrrolidine, piperidine, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio and (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C 1 -C 6 )alkyl-CO 2 , (C 1 -C 6 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl and (C 1 -C 6 )alkoxy;
or R 5 is N(R 4 ) 2 wherein R 4 is as defined above.
35 . A compound according to claim 34 , wherein the compound of formula XI is the R enantiomer
wherein R 1 is chloro and R 2 is hydrogen.
36 . A compound according to claim 34 , wherein the compound of formula XI is the R enantiomer
wherein R 1 and R 2 are hydrogen.
37 - 39 . (canceled)
40 . A compound of the formula
wherein
n is 0, 1, 2 or 3;
m is 1 or 2;
R 1 is hydrogen or halo;
each R 2 is independently hydrogen, nitro, halo, trifluoromethyl, cyano, SR 4 , OR 4 , SO 2 R 4 , OCOR 5 , or (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by hydroxy, halo, cyano, N(R 4 ) 2 , SR 4 , trifluoromethyl, OR 4 , (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, NR 4 COR 5 , COR 5 , SO 2 R 5 , OCOR 5 , NR 4 SO 2 R 5 and NR 4 CO 2 R 4 ;
R 4 and R 5 , for each occurrence, are each independently selected from hydrogen, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 6 -C 10 )aryl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heteroaryl or (C 1 -C 6 )aryl wherein the alkyl group is optionally substituted by the group consisting of hydroxy, halo, carboxy, (C 1 -C 10 )alkyl-CO 2 , (C 1 -C 10 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 10 )alkoxy, or (C 1 -C 6 )alkyl; and wherein the aryl, heterocycloalkyl and heteroaryl groups are optionally substituted by one to four groups consisting of halo, nitro, oxo, ((C 1 -C 6 )alkyl) 2 amino, pyrrolidine, piperidine, (C 1 -C 10 )alkyl, (C 1 -C 10 )alkoxy, (C 1 -C 10 )alkylthio and (C 1 -C 10 )alkyl wherein the alkyl group is optionally substituted by one to four groups selected from hydroxy, halo, carboxy, (C 1 -C 6 )alkyl-CO 2 , (C 1 -C 6 )alkylsulfonyl, (C 3 -C 8 )cycloalkyl and (C 1 -C 6 )alkoxy;
or R 5 is N(R 4 ) 2 wherein R 4 is as defined above.
41 . A compound according to claim 40 , wherein m is 2, R 1 is chloro, and R 2 is hydrogen.
42 . A compound according to claim 40 , wherein m is 2 and R 2 and R 3 are hydrogen.
43 . A compound according to claim 40 , wherein the compound of formula XVII is the R enantiomer
wherein m is 2 and R 1 and R 2 are hydrogen.
44 . A compound according to claim 40 , wherein the compound of formula XVII is the R enantiomer
wherein m is 2, R 1 is chloro and R 2 are hydrogen.
45 . A compound of the formula
wherein R 1 is hydrogen or chloro and BOC is tert-butoxycarbonyl.
46 . A compound of the formula
wherein R 1 is hydrogen or chloro and BOC is tert-butoxycarbonyl.
47 . A compound of the formula
wherein BOC is tert-butoxycarbonyl.
48 . A compound of the formula
wherein R 1 is hydrogen or halo.Join the waitlist — get patent alerts
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