US2018170918A1PendingUtilityA1
Methods of synthesizing a difluorolactam analog
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
Inventors:Stephen Douglas BarrettJoseph Michael ColomboBradlee David GermainAndriy KornilovJames Bernard KramerAdam Uzieblo
A61P 43/00A61P 25/04A61P 27/06C07D 207/273C07D 333/38C07D 409/06A61P 19/10C07F 9/4006C07D 498/04C07B 39/00
54
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to processes and intermediates for preparing compounds of formula (IA), wherein R 1 , R 4 , R 5 , R 6 , and L 1 are as defined herein. Compounds of formula (IA) have been found useful as EP 4 receptor agonists useful in the treatment of glaucoma, osteoporosis, neuropathic pain, and related disorders.
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method of preparing a compound of formula (IA)
or a pharmaceutically acceptable salt thereof wherein:
L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n1 -G 2 -(CH 2 ) p —, —(CH 2 ) n2 —C≡C-G 2 -, or —(CH 2 ) n2 —C(R 12 )═C(R 12 )-G 2 -, wherein n1 is 2, 3, 4, or 5, n2 is 1, 2, or 3, p is 0, 1, 2, or 3, and n1+p=2, 3, 4, 5, or 6;
G 2 is
R 1 is a carboxylic acid or a protected carboxylic acid;
R 12 , at each occurrence, is independently H or C 1 -C 4 alkyl;
R 4 and R 5 are each independently H or C 1 -C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl;
R 6 is aryl, heteroaryl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy;
L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; and
R 7 is C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy;
the method comprising reacting a compound of formula (10),
with a carbonyl-reducing agent; and when R 1 is a protected carboxylic acid, optionally deprotecting the protected carboxylic acid.
2 . The method of claim 1 wherein:
L 1 is n-hexylene, —(CH 2 ) 3 -G 2 -, —CH 2 —C≡C-G 2 -, or —CH 2 —C(H)═C(H)-G 2 -;
G 2 is
R 4 and R 5 are each independently H or C 1 -C 4 alkyl;
R 6 is phenyl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the phenyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and
R 7 is phenyl, which is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
3 . The method of claim 2 wherein:
L 1 is —(CH 2 ) 3 -G 2 -;
G 2 is
R 4 and R 5 are each independently H or methyl;
R 6 is —CH 2 —C≡C—C 1 -C 4 alkyl or L 3 -R 7 ;
L 3 is C 3 -C 6 alkylene; and
R 7 is phenyl.
4 . The method of claim 3 wherein R 4 is methyl and R 5 is H.
5 . The method of claim 3 wherein R 4 is H and R 5 is methyl.
6 . The method of any of claims 1 - 5 wherein the carbonyl-reducing agent comprises a mixture of
and catecholborane.
7 . The method of any of claims 1 - 5 further comprising reacting a compound of formula (8) with a compound of formula (9) in the presence of a trialkylamine base and lithium chloride to produce the compound of formula (10), wherein R 1 is a protected carboxylic acid; and R 15 is C 1 -C 6 alkyl.
8 . The method of claim 7 further comprising reacting a compound of formula (7) with an oxidizing agent to produce the compound of formula (8).
9 . The method of claim 8 wherein the oxidizing agent is Dess-Martin periodinane.
10 . The method of claim 8 further comprising removing a protecting group PG from a compound of formula (6) to produce the compound of formula (7).
11 . The method of claim 10 wherein PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
12 . The method of claim 10 further comprising reacting a compound of formula (5) with a base and a compound of formula X 1 -L 1 -R 1 to produce the compound of formula (6), wherein X 1 is a leaving group selected from the group consisting of bromo, chloro, iodo, an alkylsulfonate, a fluoroalkylsulfonate, and an arylsulfonate.
13 . The method of claim 12 wherein the base is lithium hydride, sodium hydride, or potassium hydride; PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
14 . The method of claim 12 further comprising adding a protecting group PG to a compound of formula (4) to produce the compound of formula (5).
15 . The method of claim 14 wherein PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
16 . A method of preparing a compound of formula (10) comprising reacting a compound of formula (8) with a compound of formula (9) in the presence of a trialkylamine base and lithium chloride;
wherein:
L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n1 -G 2 -(CH 2 ) p —, —(CH 2 ) n2 —C≡C-G 2 -, or —(CH 2 ) n2 —C(R 12 )═C(R 12 )-G 2 -, wherein n1 is 2, 3, 4, or 5, n2 is 1, 2, or 3, p is 0, 1, 2, or 3, and n1+p=2, 3, 4, 5, or 6;
G 2 is
R 1 is a protected carboxylic acid;
R 12 , at each occurrence, is independently H or C 1 -C 4 alkyl;
R 4 and R 5 are each independently H or C 1 -C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl;
R 6 is aryl, heteroaryl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy;
L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene;
R 7 is C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and
R 15 is C 1 -C 6 alkyl.
17 . The method of claim 16 wherein:
L 1 is n-hexylene, —(CH 2 ) 3 -G 2 -, —CH 2 —C≡C-G 2 -, or —CH 2 —C(H)═C(H)-G 2 -;
G 2 is
R 4 and R 5 are each independently H or C 1 -C 4 alkyl;
R 6 is phenyl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the phenyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and
R 7 is phenyl, which is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
18 . The method of claim 17 wherein:
L 1 is —(CH 2 ) 3 -G 2 -;
R 4 and R 5 are each independently H or methyl;
R 6 is —CH 2 —C≡C—C 1 -C 4 alkyl or L 3 -R 7 ;
L 3 is C 3 -C 6 alkylene; and
R 7 is phenyl.
19 . The method of any of claims 16 - 18 further comprising reacting a compound of formula (7) with an oxidizing agent to produce the compound of formula (8).
20 . The method of claim 19 wherein the oxidizing agent is Dess-Martin periodinane.
21 . The method of claim 19 further comprising removing a protecting group PG from a compound of formula (6) to produce the compound of formula (7).
22 . The method of claim 21 wherein PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
23 . The method of claim 21 further comprising reacting a compound of formula (5) with a base and a compound of formula X 1 -L 1 -R 1 to produce the compound of formula (6), wherein X 1 is a leaving group selected from the group consisting of bromo, chloro, iodo, an alkylsulfonate, a fluoroalkylsulfonate, and an arylsulfonate.
24 . The method of claim 23 wherein the base is lithium hydride, sodium hydride, or potassium hydride; PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
25 . The method of claim 23 further comprising adding a protecting group PG to a compound of formula (4) to produce the compound of formula (5).
26 . The method of claim 25 wherein PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
27 . A method of preparing a compound of formula (8), comprising reacting a compound of formula (7) with an oxidizing agent,
wherein:
L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n1 -G 2 -(CH 2 ) p —, —(CH 2 ) n2 —C≡C-G 2 -, or —(CH 2 ) n2 —C(R 12 )═C(R 12 )-G 2 -, wherein n1 is 2, 3, 4, or 5, n2 is 1, 2, or 3, p is 0, 1, 2, or 3, and n1+p=2, 3, 4, 5, or 6;
G 2 is
R 1 is a protected carboxylic acid; and
R 12 , at each occurrence, is independently H or C 1 -C 4 alkyl.
28 . The method of claim 27 wherein:
L 1 is n-hexylene, —(CH 2 ) 3 -G 2 -, —CH 2 —C≡C-G 2 -, or —CH 2 —C(H)═C(H)-G 2 -; and
G 2 is
29 . The method of claim 28 wherein:
L 1 is —(CH 2 ) 3 -G 2 -.
30 . The method of any of claims 27 - 29 wherein the oxidizing agent is Dess-Martin periodinane.
31 . The method of any of claims 27 - 29 further comprising removing a protecting group PG from a compound of formula (6) to produce the compound of formula (7).
32 . The method of claim 31 wherein PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
33 . The method of claim 32 wherein PG is —Si(R 21 ) 3 and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
34 . The method of claim 31 further comprising reacting a compound of formula (5) with a base and a compound of formula X 1 -L 1 -R 1 to produce the compound of formula (6), wherein X 1 is a leaving group selected from the group consisting of bromo, chloro, iodo, an alkylsulfonate, a fluoroalkylsulfonate, and an arylsulfonate.
35 . The method of claim 34 wherein the base is sodium hydride, lithium hydride, or potassium hydride; PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
36 . The method of claim 34 further comprising adding a protecting group PG to a compound of formula (4) to produce the compound of formula (5).
37 . The method of claim 36 wherein PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
38 . The method of claim 37 wherein PG is —Si(R 21 ) 3 and R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
39 . A method of preparing a compound of formula (6) comprising reacting a compound of formula (5) with a base and a compound of formula X 1 -L 1 -R 1 ,
wherein:
X 1 is a leaving group selected from the group consisting of bromo, chloro, iodo, an alkylsulfonate, a fluoroalkylsulfonate, and an arylsulfonate;
PG is a protecting group;
L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n1 -G 2 -(CH 2 ) p —, —(CH 2 ) n2 —C≡C-G 2 -, or —(CH 2 ) n2 —C(R 12 )═C(R 12 )-G 2 -, wherein n1 is 2, 3, 4, or 5, n2 is 1, 2, or 3, p is 0, 1, 2, or 3, and n1+p=2, 3, 4, 5, or 6;
G 2 is
R 1 is a protected carboxylic acid; and
R 12 , at each occurrence, is independently H or C 1 -C 4 alkyl.
40 . The method of claim 39 wherein:
L 1 is n-hexylene, —(CH 2 ) 3 -G 2 -, —CH 2 —C≡C-G 2 -, or —CH 2 —C(H)═C(H)-G 2 -;
G 2 is
PG is —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and
R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
41 . The method of claim 40 wherein:
L 1 is —(CH 2 ) 3 -G 2 -; and
PG is —Si(R 21 ) 3 .
42 . The method of any one of claims 39 - 41 wherein the base is sodium hydride, lithium hydride, or potassium hydride.
43 . A method of preparing a compound of formula (4) by reacting the compound of formula (2) with an acid, wherein R 13 is independently C 1 -C 3 alkyl or phenyl, or the R 13 groups, together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl.
44 . The method of claim 43 wherein the acid is an acidic cation exchange resin.
45 . A method of preparing a compound of formula (2) from a compound of formula (1) comprising reacting a compound of formula (1) with a base and a fluorinating agent, wherein each R 13 is independently C 1 -C 3 alkyl or phenyl, or the R 13 groups, together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl.
46 . The method of claim 45 wherein the reacting a compound of formula (1) with a base and a fluorinating agent comprises reacting the compound of formula (1) with a first base and a fluorinating agent and a second base and a fluorinating agent.
47 . The method of claim 45 wherein the reacting a compound of formula (1) with a base and fluorinating agent comprises:
adding a solution of sec-butyl lithium in an organic solvent to a solution of the compound of formula (1) in an organic solvent to produce a first reaction mixture;
adding N-fluorobenzene sulfonimide to the first reaction mixture to produce a second reaction mixture;
adding a solution of a base selected from the group consisting of lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and lithium diisopropylamide, in an organic solvent to the second reaction mixture to produce a third reaction mixture; and
adding N-fluorobenzene sulfonimide to the third reaction mixture.
48 . The method of claim 45 further comprising preparing the compound of formula (1) from a compound of formula (0) by reacting the compound of formula (0) with a compound of formula
in the presence of an acid, wherein each R 13 is independently C 1 -C 3 alkyl or phenyl, or the R 13 groups, together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl; and R 14 is methyl or ethyl.
49 . The method of any of claims 45 - 48 wherein R 13 is methyl.
50 . A compound of formula (10)
or salts thereof wherein:
L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n1 -G 2 -(CH 2 ) p —, —(CH 2 ) n2 —C≡C-G 2 -, or —(CH 2 ) n2 —C(R 12 )═C(R 12 )-G 2 -, wherein n1 is 2, 3, 4, or 5, n2 is 1, 2, or 3, p is 0, 1, 2, or 3, and n1+p=2, 3, 4, 5, or 6;
G 2 is
R 1 is a carboxylic acid or a protected carboxylic acid;
R 12 , at each occurrence, is independently H or C 1 -C 4 alkyl;
R 4 and R 5 are each independently H or C 1 -C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl;
R 6 is aryl, heteroaryl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy;
L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene; and
R 7 is C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
51 . The compound of claim 50 , or salts thereof, wherein:
L 1 is n-hexylene, —(CH 2 ) 3 -G 2 -, —CH 2 —C≡C-G 2 -, or —CH 2 —C(H)═C(H)-G 2 -; G 2 is
R 4 and R 5 are each independently H or C 1 -C 4 alkyl;
R 6 is phenyl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the phenyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and
R 7 is phenyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
52 . The compound of claim 51 wherein:
L 1 is —(CH 2 ) 3 -G 2 -;
R 4 is methyl;
R 5 is hydrogen;
R 6 is —CH 2 —C≡C—C 1 -C 4 alkyl or L 3 -R 7 ;
L 3 is C 3 -C 6 alkylene; and
R 7 is phenyl.
53 . The compound of claim 51 wherein:
L 1 is —(CH 2 ) 3 -G 2 -;
R 4 is hydrogen;
R 5 is methyl;
R 6 is —CH 2 —C≡C—C 1 -C 4 alkyl or L 3 -R 7 ;
L 3 is C 3 -C 6 alkylene; and
R 7 is phenyl.
54 . A compound of formula (6.1)
wherein:
L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n1 -G 2 -(CH 2 ) p —, —(CH 2 ) n2 —C≡C-G 2 -, or —(CH 2 ) n2 —C(R 12 )═C(R 12 )-G 2 -, wherein n1 is 2, 3, 4, or 5, n2 is 1, 2, or 3, p is 0, 1, 2, or 3, and n1+p=2, 3, 4, 5, or 6;
G 2 is
R 1 is a protected carboxylic acid;
R 12 , at each occurrence, is independently H or C 1 -C 4 alkyl; and
R 20 is H or a hydroxyl protecting group.
55 . The compound of claim 54 wherein:
L 1 is n-hexylene, —(CH 2 ) 3 -G 2 -, —CH 2 —C≡C-G 2 -, or —CH 2 —C(H)═C(H)-G 2 -;
G 2 is
R 20 is H, —Si(R 21 ) 3 , 1-ethoxyethyl, or tetrahydro-2H-pyran-2-yl; and
R 21 , at each occurrence, is independently selected from C 1 -C 4 alkyl and phenyl.
56 . The compound of claim 55 wherein
L 1 is —(CH 2 ) 3 -G 2 -.
57 . A compound of formula (2)
wherein each R 13 is independently C 1 -C 3 alkyl or phenyl, or the R 13 groups, together with the carbon to which they are attached, form a C 3 -C 6 cycloalkyl.
58 . The compound of claim 57 wherein R 13 is methyl.
59 . A compound of formula (9)
wherein:
R 4 and R 5 are each independently H or C 1 -C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl;
R 6 is aryl, heteroaryl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy; and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy;
L 3 is C 1 -C 6 alkylene, C 2 -C 6 alkenylene, C 2 -C 6 alkynylene;
R 7 is C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and
R 15 is C 1 -C 6 alkyl.
60 . The compound of claim 59 wherein:
R 4 and R 5 are each independently H or C 1 -C 4 alkyl;
R 6 is phenyl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the phenyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and
R 7 is phenyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 -C 3 haloalkyl, cyano, halogen, C 1 -C 3 alkoxy, C 1 -C 3 haloalkoxy, and —C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
61 . The compound of claim 60 wherein:
R 4 is methyl;
R 5 is hydrogen;
R 6 is —CH 2 —C≡C—C 1 -C 4 alkyl or L 3 -R 7 ;
L 3 is C 3 -C 6 alkylene;
R 7 is phenyl; and
R 15 is methyl or ethyl.
62 . The compound of claim 60 wherein:
R 4 is hydrogen;
R 5 is methyl;
R 6 is —CH 2 —C≡C—C 1 -C 4 alkyl or L 3 -R 7 ;
L 3 is C 3 -C 6 alkylene;
R 7 is phenyl; and
R 15 is methyl or ethyl.
63 . A compound of formula X 1 -L 1 -R 1 , wherein:
X 1 is selected from the group consisting of bromo, chloro, iodo, an alkylsulfonate, a fluoroalkylsulfonate, and an arylsulfonate; L 1 is
a) C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene; or
b) —(CH 2 ) n1 -G 2 -(CH 2 ) p —, —(CH 2 ) n2 —C≡C-G 2 -, or —(CH 2 ) n2 —C(R 12 )═C(R 12 )-G 2 -, wherein n1 is 2, 3, 4, or 5, n2 is 1, 2, or 3, p is 0, 1, 2, or 3, and n1+p=2, 3, 4, 5, or 6;
G 2 is
R 1 is a protected carboxylic acid; and
R 12 is H or C 1 -C 4 alkyl.
64 . The compound of claim 63 wherein:
L 1 is n-hexylene, —(CH 2 ) 3 -G 2 -, —CH 2 —C≡C-G 2 -, or —CH 2 —C(H)═C(H)-G 2 -; and
G 2 is
65 . The compound of claim 64 wherein:
L 1 is —(CH 2 ) 3 -G 2 -.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.