U.S. patent application number 17/738872 was filed with the patent office on 2022-08-25 for heterocyclic prolinamide derivatives.
This patent application is currently assigned to ORION OPHTHALMOLOGY LLC. The applicant listed for this patent is ORION OPHTHALMOLOGY LLC. Invention is credited to Jinyue Ding, Maxim Epifanov, Robert Gomez, Renata Oballa, David Andrew Powell.
Application Number | 20220267306 17/738872 |
Document ID | / |
Family ID | |
Filed Date | 2022-08-25 |
United States Patent
Application |
20220267306 |
Kind Code |
A1 |
Gomez; Robert ; et
al. |
August 25, 2022 |
HETEROCYCLIC PROLINAMIDE DERIVATIVES
Abstract
This invention is directed to novel heterocyclic prolinamide
derivatives of Formula I, ##STR00001## and pharmaceutically
acceptable salts, solvates, solvates of the salt and prodrugs
thereof, useful in the prevention (e.g., delaying the onset of or
reducing the risk of developing) and treatment (e.g., controlling,
alleviating, or slowing the progression of) of age-related macular
degeneration (AMD) and related diseases of the eye. These diseases
include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy,
retinopathy of prematurity, polypoidal choroidal vasculopathy, and
degeneration of retinal or photoreceptor cells. The invention
disclosed herein is further directed to methods of prevention,
slowing the progress of, and treatment of dry-AMD, wet-AMD, and
geographic atrophy, diabetic retinopathy, retinopathy of
prematurity, polypoidal choroidal vasculopathy, and degeneration of
retinal or photoreceptor cells, comprising: administration of a
therapeutically effective amount of compound of the invention. The
compounds of the invention are inhibitors of HTRA1. Thus, the
compounds of the invention are useful in the prevention and
treatment of a wide range of diseases mediated (in whole or in
part) by HTRA1. The compounds of the invention are also useful for
inhibiting HTRA1 protease activity in an eye or locus of an
arthritis or related condition.
Inventors: |
Gomez; Robert; (North
Vancouver, CA) ; Ding; Jinyue; (Burnaby, CA) ;
Oballa; Renata; (Coquitlam, CA) ; Powell; David
Andrew; (Vancouver, CA) ; Epifanov; Maxim;
(Vancouver, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ORION OPHTHALMOLOGY LLC |
New York |
NY |
US |
|
|
Assignee: |
ORION OPHTHALMOLOGY LLC
New York
NY
|
Appl. No.: |
17/738872 |
Filed: |
May 6, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16312247 |
Dec 20, 2018 |
11377439 |
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PCT/US2017/037768 |
Jun 15, 2017 |
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17738872 |
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62352963 |
Jun 21, 2016 |
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International
Class: |
C07D 401/14 20060101
C07D401/14; C07D 405/14 20060101 C07D405/14; C07D 409/14 20060101
C07D409/14; C07D 413/14 20060101 C07D413/14; C07D 417/14 20060101
C07D417/14; C07D 471/04 20060101 C07D471/04 |
Claims
1. A compound of Formula (I): ##STR00217## or a pharmaceutically
acceptable salt, solvate, solvate of the salt or prodrug thereof
wherein: W is selected from the group consisting of: --B(OH).sub.2
and --C(O)C(O)NR.sup.7R.sup.8; X is selected from the group
consisting of: --O--, --S(O).sub.p-- and --N(C(O)OR.sup.6)--; Y is
selected from the group consisting of: --C(O)--, --SO.sub.2--, and
--NHC(O)--; R.sup.1 is selected from the group consisting of: (a)
--(CH.sub.2).sub.0-6-aryl, (b) --(CH.sub.2).sub.0-6-heteroaryl, (c)
--(CH.sub.2).sub.0-6--C.sub.3-8cycloalkyl optionally substituted
with phenyl, and (d) --(CH.sub.2).sub.0-6-heterocyclyl optionally
substituted with phenyl or oxo, wherein the aryl and heteroaryl of
choices (a) and (b) are each optionally substituted with 1 to 3
substituents independently selected from the group consisting of:
(i) -halogen, (ii) --CN, (iii) --C.sub.1-6alkyl, (iv)
--C.sub.0-6alkyl-R.sup.5, (v) --C.sub.2-6alkenyl, (vi)
--C.sub.2-6alkynyl, (vii) --C(O)R.sup.7, (viii) --CO.sub.2R.sup.7,
(ix) --CONR.sup.7R.sup.8, (x) --OH, (xi) --O--C.sub.1-6alkyl, (xii)
--O--C.sub.0-6alkyl-R.sup.5, (xiii) --SH, (xiv)
--S(O).sub.p--C.sub.1-6alkyl, (xv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, (xvi)
--S(O).sub.2NR.sup.7R.sup.8, (xvii) --NO.sub.2, (xviii)
--NR.sup.7R.sup.8, (xix) --NHC(O)R.sup.7, (xx) --NHC(O)OR.sup.7,
(xxi) --NHC(O)NR.sup.7R.sup.8, (xxii) --NHSO.sub.2C.sub.1-6alkyl,
and (xxiii) --NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the
alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv),
(xxii) and (xxiii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl; R.sup.2 is selected from the group
consisting of: (a) --C.sub.3-8alkyl and (b)
--C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group of
choices (a) and (b) is optionally substituted with 1 to 5
substituents independently selected from: (i) -halogen, (ii)
-haloC.sub.1-4alkyl, (iii) --NR.sup.7R.sup.8, (iv) --OH, (v)
--O--C.sub.1-4alkyl, (vi) --SH, (vii) --S--C.sub.1-4alkyl; (viii)
--NR.sup.7SO.sub.2C.sub.1-4alkyl, and (ix) --NR.sup.7C(O)OR.sup.7,
R.sup.3a is H, and R.sup.3b is selected from the group consisting
of: (a) --H, (b) --OH, (c) -heteroaryl, (d) --O-heteroaryl, (e)
-heterocycle, (f) -aryl, and (g) --O-aryl; wherein each of the
heteroaryl of choices (c) and (d), the heterocycle of choice (e)
and the aryl of choices (f) and (g) is optionally substituted with
1 to 3 groups independently selected from the group consisting of:
(i) -halogen, (ii) --OH, (iii) --CR.sup.10R.sup.11R.sup.12, (iv)
--(CH.sub.2).sub.0-3--NHSO.sub.2--C.sub.1-4alkyl, (v)
--(CH.sub.2).sub.0-3--SO.sub.2--C.sub.1-4alkyl, (vi)
--(CH.sub.2).sub.0-3--C(O)O--C.sub.1-4alkyl, and (vii) --CN; and
wherein the heterocycle of choice (e) is additionally optionally
substituted with 1 to 2 oxo groups; or R.sup.3a and R.sup.3b
together represent oxo; each R.sup.4 is independently selected from
the group consisting of: (a) --C.sub.1-4alkyl, (b)
-haloC.sub.1-4alkyl, (c) --OH, (d) --O--C.sub.1-4alkyl, (e)
--O-haloC.sub.1-4alkyl, and (f) -halogen; each R.sup.5 is
independently selected from the group consisting of: (a)
--C.sub.3-12cycloalkyl, (b) -aryl, (c) -heteroaryl, and (d)
-heterocyclyl, wherein each of choices (a) to (d) is optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of: (i) --C.sub.1-4alkyl, (ii) -halogen, (iii)
--NR.sup.7R.sup.8, (iv) --OH, (v) --O--C.sub.1-4alkyl, (vi) --SH,
and (vii) --S--C.sub.1-4alkyl; wherein each of the alkyl group of
choices (i), (v) and (vii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; R.sup.6 is selected from the group consisting
of: (a) --C.sub.1-6alkyl, and (b) --C.sub.0-6alkyl-aryl; each
R.sup.7 and each R.sup.8 are independently selected from the group
consisting of: (a) --H, (b) --C.sub.1-6alkyl, (c)
--C.sub.0-6alkyl-C.sub.3-12cycloalkyl, (d)
--C.sub.0-6alkyl-heterocyclyl, (e) --C.sub.0-6alkyl-heteroaryl, (f)
--C.sub.0-6alkyl-aryl, (g) --C.sub.2-6alkenyl, and (h)
--C.sub.2-6alkynyl, wherein the alkyl group of choices (b)-(f), the
alkenyl group of choice (g), the cycloalkyl group of choice (c),
and the alkynyl group of (h) is optionally substituted with 1 to 3
groups independently selected from: (i) -halogen, (ii)
--C.sub.1-4alkyl, (iii) --C(O)C.sub.1-4alkyl, (iv) --OH, (v)
--OC.sub.1-4alkyl, (vi) --SH, (vii) --SC.sub.1-4alkyl, (viii)
--NH.sub.2, (ix) --NH(C.sub.1-4alkyl), and (x)
--N(C.sub.1-4alkyl)(C.sub.1-4alkyl); or R.sup.7, R.sup.8 and the
nitrogen atom to which they are attached together form a 3- to
7-membered monocyclic or 6- to 11-membered bicyclic heterocycle
optionally having an additional heteroatom selected from O,
S(O).sub.p, and NR.sup.9, and wherein said heterocycle is
optionally substituted with 1 to 2 groups independently selected
from halogen; R.sup.9 is selected from the group consisting of: (a)
--H, (b) --C.sub.1-4alkyl, (c) --C(O)--C.sub.1-4alkyl, (d)
--C(O)NH.sub.2, (e) --C(O)--NH(C.sub.1-4alkyl), (f)
--C(O)--N(C.sub.1-4alkyl).sub.2, and (g) --C(O)O--C.sub.1-4alkyl;
R.sup.10, R.sup.11, and R.sup.12 are independently selected from
the group consisting of: H, halogen, --OH and --C.sub.1-6 alkyl; or
R.sup.10, R.sup.11 and the carbon atom to which they are attached
together form a C.sub.3-12cycloalkyl or a heterocyclyl group; k is
0, 1, 2, 3 or 4; n and m are independently selected from 0, 1, 2
and 3, with the proviso that n+m is 0, 1, 2, 3 or 4; and p is 0, 1
or 2.
2. A compound of claim 1 wherein R.sup.1 is selected from the group
consisting of: (a) -aryl, and (b) -heteroaryl, wherein the aryl and
heteroaryl of choices (a) and (b) are each optionally substituted
with 1 to 3 substituents independently selected from the group
consisting of: (i) -halogen, (ii) --CN, (iii) --C.sub.1-6alkyl,
(iv) --C.sub.0-6alkyl-R.sup.5, (v) --C.sub.2-6alkenyl, (vi)
--C.sub.2-6alkynyl, (vii) --C(O)R.sup.7, (viii) --CO.sub.2R.sup.7,
(ix) --CONR.sup.7R.sup.8, (x) --OH, (xi) --O--C.sub.1-6alkyl, (xii)
--O--C.sub.0-6alkyl-R.sup.5, (xiii) --SH, (xiv)
--S(O).sub.p--C.sub.1-6alkyl, (xv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, (xvi)
--S(O).sub.2NR.sup.7R.sup.8, (xvii) --NO.sub.2, (xviii)
--NR.sup.7R.sup.8, (xix) --NHC(O)R.sup.7, (xx) --NHC(O)OR.sup.7,
(xxi) --NHC(O)NR.sup.7R.sup.8, (xxii) --NHSO.sub.2C.sub.1-6alkyl,
and (xxiii) --NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the
alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv),
(xxii) and (xxiii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl.
3. A compound of claim 1 or claim 2 wherein R.sup.3b is selected
from the group consisting of: (a) --OH, (b) -heteroaryl, (c)
--O-heteroaryl, (d) -heterocycle, (e) -aryl, and (f) --O-aryl;
wherein each of the heteroaryl of choices (b) and (c), the
heterocycle of choice (d) and the aryl of choices (e) and (f) is
optionally substituted with 1 to 3 groups independently selected
from the group consisting of: (i) -halogen, (ii) --OH, (iii)
--CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein the
heterocycle of choice (d) is additionally optionally substituted
with 1 to 2 oxo groups; or R.sup.3a and R.sup.3b together represent
oxo.
4. A compound of any one of claims 1 through 3 wherein R.sup.3b is
selected from the group consisting of: (a) --OH, (b) -heteroaryl,
(c) --O-heteroaryl, and (d) -heterocycle, wherein each of the
heteroaryl of choices (b) and (c), and the heterocycle of choice
(d) is optionally substituted with 1 to 3 groups independently
selected from the group consisting of: (i) -halogen, (ii) --OH,
(iii) --CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein the
heterocycle of choice (d) is additionally optionally substituted
with 1 to 2 oxo groups.
5. A compound of any one of claims 1 through 4 wherein R.sup.3b is
selected from the group consisting of: (a) --OH, (b) ##STR00218##
(c) --O-heteroaryl, and (d) ##STR00219## wherein HAr is heteroaryl
and Hcyl is heterocycle, and HAr, heteroaryl of choice (c), and
Hcyl are each optionally substituted with 1 to 3 groups
independently selected from the group consisting of: (i) -halogen,
(ii) --OH, (iii) --CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein
Hcyl is additionally optionally substituted with 1 to 2 oxo
groups.
6. A compound of any one of claims 1 through 5 wherein R.sup.3b is
selected from the group consisting of: (a) ##STR00220## and (b)
##STR00221## wherein HAr is heteroaryl and Hcyl is heterocycle, and
HAr and Hcyl are each optionally substituted with 1 to 3 groups
independently selected from the group consisting of: (i) -halogen,
(ii) --OH, (iii) --CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein
Hcyl is additionally optionally substituted with 1 to 2 oxo
groups.
7. A compound of any of claims 1 through 6 wherein R.sup.2 is
--C.sub.1-6alkyl-R.sup.5, wherein the alkyl group is optionally
substituted with 1 to 3 substituents independently selected from:
(i) -halogen, (ii) -haloC.sub.1-4alkyl, (iii) --O--C.sub.1-4alkyl,
(iv) --S--C.sub.1-4alkyl.
8. A compound of any of claims 1 through 7 wherein R.sup.5 is
--C.sub.3-12cycloalkyl optionally substituted with 1 to 3
substituents independently selected from the group consisting of:
(i) --C.sub.1-4alkyl, (ii) -halogen, (iii) --O--C.sub.1-4alkyl,
(iv) --S--C.sub.1-4alkyl; wherein each of the alkyl group of
choices (i), (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl.
9. A compound of any of claims 1-8 wherein W is
--C(O)C(O)NR.sup.7R.sup.8.
10. A compound of any of claims 1-9 wherein X is --O-- or
--S(O).sub.p--.
11. A compound of claim 1 having the formula (Ia): ##STR00222## or
a pharmaceutically acceptable salt, solvate, solvate of the salt or
prodrug thereof wherein: W is selected from the group consisting
of: --B(OH).sub.2 and --C(O)C(O)NR.sup.7R.sup.8; X is --O-- or
--S(O).sub.p--; Y is selected from the group consisting of:
--C(O)--, --SO.sub.2--, and --NHC(O)--; R.sup.1 is selected from
the group consisting of: (a) -aryl, (b) -heteroaryl, wherein the
aryl and heteroaryl of choices (a) and (b) are each optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of: (i) -halogen, (ii) --CN, (iii)
--C.sub.1-6alkyl, (iv) --C.sub.0-6alkyl-R.sup.5, (v)
--C.sub.2-6alkenyl, (vi) --C.sub.2-6alkynyl, (vii) --C(O)R.sup.7,
(viii) --CO.sub.2R.sup.7, (ix) --CONR.sup.7R.sup.8, (x) --OH, (xi)
--O--C.sub.1-6alkyl, (xii) --O--C.sub.0-6alkyl-R.sup.5, (xiii)
--SH, (xiv) --S(O).sub.p--C.sub.1-6alkyl, (xv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, (xvi)
--S(O).sub.2NR.sup.7R.sup.8, (xvii) --NO.sub.2, (xviii)
--NR.sup.7R.sup.8, (xix) --NHC(O)R.sup.7, (xx) --NHC(O)OR.sup.7,
(xxi) --NHC(O)NR.sup.7R.sup.8, (xxii) --NHSO.sub.2C.sub.1-6alkyl,
and (xxiii) --NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the
alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv),
(xxii) and (xxiii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl; R.sup.3a is H and R.sup.3b is
selected from the group consisting of: (a) --OH, (b) -heteroaryl,
(c) --O-heteroaryl, (d) -heterocycle, (e) -aryl, and (f) --O-aryl;
wherein each of the heteroaryl of choices (b) and (c), the
heterocycle of choice (d) and the aryl of choices (e) and (f) is
optionally substituted with 1 to 3 groups independently selected
from the group consisting of: (i) -halogen, (ii) --OH, (iii)
--CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein the
heterocycle of choice (d) is additionally optionally substituted
with 1 to 2 oxo groups; or R.sup.3a and R.sup.3b together represent
oxo; R.sup.4 is selected from the group consisting of: (a)
--C.sub.1-4alkyl, (b) -haloC.sub.1-4alkyl, (c) --OH, (d)
--O--C.sub.1-4alkyl, (e) --O-haloC.sub.1-4alkyl, and (f) -halogen;
R.sup.5 is --C.sub.3-12cycloalkyl optionally substituted with 1 to
3 substituents independently selected from the group consisting of:
(i) --C.sub.1-4alkyl, (ii) -halogen, (iii) --O--C.sub.1-4alkyl,
(iv) --S--C.sub.1-4alkyl; wherein each of the alkyl group of
choices (i), (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; each R.sup.7 and each R.sup.8 are
independently selected from the group consisting of: (a) --H, (b)
--C.sub.1-6alkyl, (c) --C.sub.0-6alkyl-C.sub.3-12cycloalkyl, (d)
--C.sub.0-6alkyl-heterocyclyl, (e) --C.sub.0-6alkyl-heteroaryl, (f)
--C.sub.0-6alkyl-aryl, (g) --C.sub.2-6alkenyl, and (h)
--C.sub.2-6alkynyl, wherein the alkyl group of choices (b)-(f), the
alkenyl group of choice (g), the cycloalkyl group of choice (c),
and the alkynyl group of (h) is optionally substituted with 1 to 3
groups independently selected from: (i) -halogen, (ii)
--C.sub.1-4alkyl, (iii) --C(O)C.sub.1-4alkyl, (iv) --OH, (v)
--OC.sub.1-4alkyl, (vi) --SH, (vii) --SC.sub.1-4alkyl, (viii)
--NH.sub.2, (ix) --NH(C.sub.1-4alkyl), and (x)
--N(C.sub.1-4alkyl)(C.sub.1-4alkyl); or R.sup.7, R.sup.8 and the
nitrogen atom to which they are attached together form a 3- to
7-membered monocyclic or 6- to 11-membered bicyclic heterocycle
optionally having an additional heteroatom selected from O,
S(O).sub.p, and NR.sup.9, and wherein said heterocycle is
optionally substituted with 1 to 2 groups independently selected
from halogen; R.sup.9 is selected from the group consisting of: (a)
--H, (b) --C.sub.1-4alkyl, (c) --C(O)--C.sub.1-4alkyl, (d)
--C(O)NH.sub.2, (e) --C(O)--NH(C.sub.1-4alkyl), (f)
--C(O)--N(C.sub.1-4alkyl).sub.2, and (g) --C(O)O--C.sub.1-4alkyl;
R.sup.10, R.sup.11, and R.sup.12 are independently selected from
the group consisting of: H, halogen, --OH and --C.sub.1-6 alkyl; or
R.sup.10, R.sup.11 and the atom to which they are attached together
form a C.sub.3-12cycloalkyl or a heterocyclyl group; k is 0, 1, 2,
3 or 4; n and m are independently selected from 0, 1, 2 and 3, with
the proviso that n+m is 0, 1, 2, 3 or 4; p is 0, 1 or 2.
12. A compound of claim 11 wherein R.sup.3b is selected from the
group consisting of: (a) --OH, (b) ##STR00223## (c) --O-heteroaryl,
and (d) ##STR00224## wherein HAr is heteroaryl and Hcyl is
heterocycle, and HAr, heteroaryl of choice (c), and Hcyl are each
optionally substituted with 1 to 3 groups independently selected
from the group consisting of: (i) -halogen, (ii) --OH, (iii)
--CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein
Hcyl is additionally optionally substituted with 1 to 2 oxo
groups.
13. A compound of claim 11 or 12 wherein R.sup.3b is selected from
the group consisting of: (a) ##STR00225## and (b) ##STR00226##
wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr and Hcyl
are each optionally substituted with 1 to 3 groups independently
selected from the group consisting of: (i) -halogen, (ii) --OH,
(iii) --CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein
Hcyl is additionally optionally substituted with 1 to 2 oxo
groups.
14. A compound of any of claims 11 through 13 wherein W is
--C(O)C(O)NH.sub.2.
15. A compound of any of claims 11 through 14 wherein Y is
--C(O)--.
16. A compound of any one of claims 11 through 14 wherein W is
--C(O)C(O)NH.sub.2; Y is --C(O)--; and R.sup.3b is selected from
the group consisting of: (a) ##STR00227## and (b) ##STR00228##
wherein HAr is heteroaryl and Hcyl is heterocycle, and each
heteroaryl and heterocycle is optionally substituted with 1 to 3
groups independently selected from the group consisting of: (i)
-halogen, (ii) --OH, (iii) --CR.sup.10R.sup.11R.sup.12, (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and (vii) --CN; wherein the
heterocycle is additionally substituted with 1 to 2 oxo groups.
17. A compound of claim 1 having the formula (Ib): ##STR00229## or
a pharmaceutically acceptable salt, solvate, solvate of the salt or
prodrug thereof, wherein W is selected from the group consisting
of: --B(OH).sub.2 and --C(O)C(O)NR.sup.7R.sup.8; X is selected from
the group consisting of: --O--, --S(O).sub.p-- and
--N(C(O)OR.sup.6)--; Y is selected from the group consisting of:
--C(O)--, --SO.sub.2--, and --NHC(O)--; R.sup.1 is selected from
the group consisting of: (a) -aryl, (b) -heteroaryl, wherein the
aryl and heteroaryl of choices (a) and (b) are each optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of: (i) -halogen, (ii) --CN, (iii)
--C.sub.1-6alkyl, (iv) --C.sub.0-6alkyl-R.sup.5, (v)
--C.sub.2-6alkenyl, (vi) --C.sub.2-6alkynyl, (vii) --C(O)R.sup.7,
(viii) --CO.sub.2R.sup.7, (ix) --CONR.sup.7R.sup.8, (x) --OH, (xi)
--O--C.sub.1-6alkyl, (xii) --O--C.sub.0-6alkyl-R.sup.5, (xiii)
--SH, (xiv) --S(O).sub.p--C.sub.1-6alkyl, (xv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, (xvi)
--S(O).sub.2NR.sup.7R.sup.8, (xvii) --NO.sub.2, (xviii)
--NR.sup.7R.sup.8, (xix) --NHC(O)R.sup.7, (xx) --NHC(O)OR.sup.7,
(xxi) --NHC(O)N.sup.7R.sup.8, (xxii) --NHSO.sub.2C.sub.1-6alkyl,
and (xxiii) --NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the
alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv),
(xxii) and (xxiii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl; R.sup.2 is selected from the group
consisting of: (a) --C.sub.3-8alkyl and (b)
--C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group of
choices (a) and (b) is optionally substituted with 1 to 5
substituents independently selected from: (i) -halogen, (ii)
-haloC.sub.1-4alkyl, (iii) --NR.sup.2R.sup.8, (iv) --OH, (v)
--O--C.sub.1-4alkyl, (vi) --SH, (vii) --S--C.sub.1-4alkyl; (viii)
--NR.sup.7SO.sub.2C.sub.1-4alkyl, and (ix) --NR.sup.7C(O)OR.sup.7,
R.sup.4 is selected from the group consisting of: (a)
--C.sub.1-4alkyl, (b) -haloC.sub.1-4alkyl, (c) --OH, (d)
--O--C.sub.1-4alkyl, (e) --O-haloC.sub.1-4alkyl, and (f) -halogen;
R.sup.5 is selected from the group consisting of: (a)
--C.sub.3-12cycloalkyl, (b) -aryl, (c) -heteroaryl, and (d)
-heterocyclyl, wherein each of choices (a) to (d) is optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of: (i) --C.sub.1-4alkyl, (ii) -halogen, (iii)
--NR.sup.7R.sup.8, (iv) --OH, (v) --O--C.sub.1-4alkyl, (vi) --SH,
and (vii) --S--C.sub.1-4alkyl; wherein each of the alkyl group of
choices (i), (v) and (vii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; R.sup.6 is selected from the group consisting
of: (a) --C.sub.1-6alkyl, and (b) --C.sub.0-6alkyl-aryl; each
R.sup.7 and each R.sup.8 are independently selected from the group
consisting of: (a) --H, (b) --C.sub.1-6alkyl, (c)
--C.sub.0-6alkyl-C.sub.3-12cycloalkyl, (d)
--C.sub.0-6alkyl-heterocyclyl, (e) --C.sub.0-6alkyl-heteroaryl, (f)
--C.sub.0-6alkyl-aryl, (g) --C.sub.2-6alkenyl, and (h)
--C.sub.2-6alkynyl, wherein the alkyl group of choices (b)-(f), the
alkenyl group of choice (g), the cycloalkyl group of choice (c),
and the alkynyl group of (h) is optionally substituted with 1 to 3
groups independently selected from: (i) -halogen, (ii)
--C.sub.1-4alkyl, (iii) --C(O)C.sub.1-4alkyl, (iv) --OH, (v)
--OC.sub.1-4alkyl, (vi) --SH, (vii) --SC.sub.1-4alkyl, (viii)
--NH.sub.2, (ix) --NH(C.sub.1-4alkyl), and (x)
--N(C.sub.1-4alkyl)(C.sub.1-4alkyl); or R.sup.7, R.sup.8 and the
nitrogen atom to which they are attached together form a 3- to
7-membered monocyclic or 6- to 11-membered bicyclic heterocycle
optionally having an additional heteroatom selected from O,
S(O).sub.p, and NR.sup.9, and wherein said heterocycle is
optionally substituted with 1 to 2 groups independently selected
from halogen; R.sup.9 is selected from the group consisting of: (a)
--H, (b) --C.sub.1-4alkyl, (c) --C(O)--C.sub.1-4alkyl, (d)
--C(O)NH.sub.2, (e) --C(O)--NH(C.sub.1-4alkyl), (f)
--C(O)--N(C.sub.1-4alkyl).sub.2, and (g) --C(O)O--C.sub.1-4alkyl;
R.sup.10, R.sup.11, and R.sup.12 are independently selected from
the group consisting of: H, halogen, --OH and --C.sub.1-6 alkyl; or
R.sup.10, R.sup.11 and the carbon atom to which they are attached
together form a C.sub.3-12cycloalkyl or a heterocyclyl group; k is
0, 1, 2, 3 or 4; n and m are independently selected from 0, 1, 2
and 3, with the proviso that n+m is 0, 1, 2, 3 or 4; p is 0, 1 or
2.
18. A compound of claim 17 wherein R.sup.2 is
--C.sub.1-3alkyl-R.sup.5, and R.sup.5 is --C.sub.3-12cycloalkyl,
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of: (i) --C.sub.1-4alkyl, (ii)
-halogen, (iii) --O--C.sub.1-4alkyl, (iv) --S--C.sub.1-4alkyl;
wherein each of the alkyl group of choices (i), (iii) and (iv) is
optionally substituted with 1 to 5 substituents independently
selected from -halogen, -haloC.sub.1-4alkyl, --OH,
--O--C.sub.1-4alkyl, --SH and --S--C.sub.1-4alkyl.
19. A compound of any of claims 17 through 18 wherein W is
--C(O)C(O)NH.sub.2; X is --O-- or --S(O).sub.p--; and Y is
--C(O)--.
20. A compound of any of claims 1 through 19 wherein R.sup.1 is
selected from the group consisting of: (e) phenyl, (f) naphthyl,
(g) 5- or 6-membered monocyclic heteroaryl ring, said ring having a
heteroatom selected from N, O and S, and optionally 1, 2 or 3
additional N atoms; and (h) 8-, 9-, or 10-membered fused bicyclic
heteroaryl ring, said ring having a heteroatom selected from N, O
and S, and optionally 1, 2 or 3 additional N atoms; wherein each of
choices (a)-(d) is optionally substituted with 1 or 2 substituents
independently selected from the group consisting of: (vi) -halogen,
(vii) --CONR.sup.7R.sup.9, (viii) --S(O).sub.p--C.sub.1-6alkyl,
(ix) --S(O).sub.p--C.sub.0-6alkyl-R.sup.5, (x)
--S(O).sub.2NR.sup.7R.sup.8, wherein each of the alkyl group of
choices (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl.
21. A compound of any of claims 1 through 20 wherein n and m are
each 1, and k is 0.
22. A compound of claim 1 having the formula (Ic): ##STR00230## or
a pharmaceutically acceptable salt, solvate, solvate of the salt or
prodrug thereof, wherein X is O or S(O).sub.n; R.sup.1 is selected
from the group consisting of: (i) phenyl, (j) naphthyl, (k) 5- or
6-membered monocyclic heteroaryl ring, said ring having a
heteroatom selected from N, O and S, and optionally 1, 2 or 3
additional N atoms; and (l) 8-, 9-, or 10-membered fused bicyclic
heteroaryl ring, said ring having a heteroatom selected from N, O
and S, and optionally 1, 2 or 3 additional N atoms; wherein each of
choices (a)-(d) is optionally substituted with 1 or 2 substituents
independently selected from the group consisting of: (xi) -halogen,
(xii) --CONR.sup.7R.sup.8, (xiii) --S(O).sub.p--C.sub.1-6alkyl,
(xiv) --S(O).sub.p--C.sub.0-6alkyl-R.sup.5, (xv)
--S(O).sub.2NR.sup.7R.sup.8, wherein each of the alkyl group of
choices (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl.
23. A compound of claim 22 wherein R.sup.1 is selected from
naphthyl, imidazo[1,2-a]pyridinyl, quinolinyl, indazolyl,
benzotriazolyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl,
benzofuranyl, indolyl, benzimidazolyl, and isoquinolinone.
24. A compound of claim 22 wherein R.sup.1 is phenyl optionally
substituted with 1 or 2 substituents independently selected from
the group consisting of: (vi) -halogen, (vii) --CONR.sup.7R.sup.8,
(viii) --S(O).sub.p--C.sub.1-6alkyl, (ix)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, (x)
--S(O).sub.2NR.sup.7R.sup.8, wherein each of the alkyl group of
choices (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl.
25. A compound of claim 1 selected from the group consisting of:
tert-butyl
4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino--
2-oxoacetyl)piperidine-1-carboxylate;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tr-
iazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4--
cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,-
3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4--
((2-amino-2-oxoethyl)sulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(1-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(difluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(trifluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzamido)propan-
oyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbo-
xamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-3-cyclohexyl-2-(4-(2-hydroxypropan-2-yl)benzamido)propanoyl)-4-(5-(2-hyd-
roxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzamido)propanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((2R)-3-cy-
clohexyl-2-(4-(2,2,2-trifluoro-1-hydroxyethyl)benzamido)propanoyl)-4-(5-(2-
-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]isoxazole-3-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]oxazole-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]thiazole-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(be-
nzofuran-5-carboxamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-6-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-fluorobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2-
,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(3-hydroxyoxetan-3-yl)benzamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-6-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-6-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-fluoro-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxy-
propan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-methyl-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxy-
propan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(cyclopentylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-y-
l)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((trifluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((2,2-difluoroethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hyd-
roxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-sulfamoylbenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H--
1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxy-
propan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N,N-diethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(2-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4--
(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4--
(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hyd-
roxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2--
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2--
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan--
2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(-
5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-phenylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3--
triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(4-(trifluoromethyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(1-methyl-1H-indol-4-yl)ureido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3--
(3-chloro-4-fluorophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-cyclohexylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,-
2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(naphthalen-1-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(4-phenyltetrahydro-2H-pyran-4-yl)ureido)propanoyl)-4-(5-(2-h-
ydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3--
benzylureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3--
triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3--
(4-cyanophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(4-(methylsulfonyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3,4-difluorophenylsulfonamido)propanoyl)-4-(5-(2-hydroxypropan--
2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(difluoromethoxy)phenylsulfonamido)propanoyl)-4-(5-(2-hydroxy-
propan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazo-
l-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)py-
rrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N--((R)-4-(2-amin-
o-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1--
yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N--((S)-4-(2-amin-
o-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1--
yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,-
3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)picolinamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-oxo-1,2-dihydroisoquinoline-3-carbo-
xamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-3-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2--
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydr-
oxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-2-methyl-2H-benzo[d][1,2,3]triazole-5-
-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-6-
-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-5-
-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxam-
ide;
N.sup.1--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thi-
opyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)p-
yrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-
-benzamido-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tri-
azol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)isonicotinamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-
-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H1-thiopyran-4-yl)-1-((R)--
3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl-
)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxam-
ide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H1-thiopyran-4-yl)-1-(-
(R)-3-cyclohexyl-2-(4-(N-(oxetan-3-yl)sulfamoyl)benzamido)propanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-methylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((cyclopropylmethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-
-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(4-((4-acetylpiperazin-1-yl)sulfonyl)benzamido)-3-cycloh-
exylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(-
5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(pyrrolidine-1-carbonyl)benzamido)propanoyl)-4-(5-(2-hydr-
oxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-
-(4-(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N.sup.1--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyr-
an-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrro-
lidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-N.sup.4,N.sup.4-dimethylterepht-
halamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-
-1-((R)-3-cyclohexyl-2-(4-(N-(1-methylcyclopropyl)sulfamoyl)benzamido)prop-
anoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-car-
boxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-
-1-((R)-3-cyclohexyl-2-(4-((4-methylpiperazin-1-yl)sulfonyl)benzamido)prop-
anoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-car-
boxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-
-1-((R)-2-(4-(azetidin-1-ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hyd-
roxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-
-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propanoyl)-4-
-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide-
;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)--
3-cyclohexyl-2-(4-(N-(tetrahydro-2H-thiopyran-4-yl)sulfamoyl)benzamido)pro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl-
)-1-((R)-3-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)-
propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-
-carboxamide;
(2S,4S)-1-((R)-2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)benzamido)--
3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-
-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbo-
xamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-3-cyclohexyl-2-(4-(N-(3,3-dimethyl-2-oxobutyl)sulfamoyl)benzamido)pr-
opanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-c-
arboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino--
2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2--
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl-
)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxam-
ide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro--
2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol--
1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamid-
e;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-
-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1--
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carboxami-
de;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-
-4-yl)-1-((R)-2-(4-cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide-
;
N.sup.1--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahyd-
ro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triaz-
ol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-nitrobenzamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-(4-bromobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-(4-chloro-2,5-difluorobenzamido)-3-cyclohexylpropanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(3,4-dichlorobenzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-6-hydroxynicotinamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-hydroxyisoquinoline-3-c-
arboxamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-fluoroquinoline-3-carbo-
xamide;
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahyd-
ro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triaz-
ol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-chloroquinoline--
3-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)--
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamid-
e;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran--
4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-
-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(spiro[3.3]heptan-2-yl)sulfamoyl)benzam-
ido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidi-
ne-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)pro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-th-
iopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)p-
ropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2--
carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-(4-(N-(tert-butyl)sulfamoyl)benzamido)-3-cyclohexylpropanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-
-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-phenylsulfamoyl)benzamido)propanoyl)-4--
(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-methylsulfamoyl)benzamido)pr-
opanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-c-
arboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-ethylsulfamoyl)benzamido)pro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide;
(2S,4R)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-th-
iopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopentylsulfamoyl)benzamido)p-
ropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2--
carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamido)propano-
yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbox-
amide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopy-
ran-4-yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)--
1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4--
(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)tetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tri-
azol-1-yl)pyrrolidine-2-carboxamide;
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1-oxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1-
,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-
-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N--((R)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-
-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N--((S)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-
-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N--((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N--((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N--((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)--N--((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide;
(S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoac-
etyl)tetrahydro-2H-pyran-4-yl)-4-oxopyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(6-oxopyridazin-1(6H)-yl)pyrrolidine--
2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin--
2(3H)-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(1,3-dioxoisoindolin-2-yl)pyrrolidine-
-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-((5-methylisoxazol-3-yl)oxy)pyrrolidi-
ne-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-chloro-6-oxopyridazin-1(6H)-yl)pyr-
rolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2-oxopyridin-1(2H)-yl)pyrrolidine-2--
carboxamide; and
(4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro--
2H-pyran-4-yl)boronic acid; or a pharmaceutically acceptable salt,
solvate, salt of the solvate, or prodrug thereof.
26. A pharmaceutical composition comprising a compound of any one
of claims 1-25 and a pharmaceutically acceptable carrier.
27. A method of preventing, or treating a disease of the eye
selected from dry-AMD, wet-AMD, geographic atrophy, diabetic
retinopathy, retinopathy of prematurity, polypoidal choroidal
vasculopathy, and degeneration of retinal or photoreceptor cells,
comprising: administering to a subject in need thereof a
therapeutically effective amount of a compound according to claim
1-25 or a pharmaceutically acceptable salt, solvate, solvate of the
salt or prodrug thereof, or the pharmaceutical composition of claim
26.
28. The method of preventing a disease of the eye, according to
claim 27 wherein the method of prevention is selected from delaying
the onset of disease and reducing the risk of developing a disease
of the eye, wherein the disease of the eye is selected from
dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy,
retinopathy of prematurity, polypoidal choroidal vasculopathy, and
degeneration of retinal or photoreceptor cells.
29. The method of treating a disease of the eye according to claim
27 wherein the method is selected from controlling, alleviating,
and slowing the progression of, wherein the disease is selected
from dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy,
retinopathy of prematurity, polypoidal choroidal vasculopathy, and
degeneration of retinal or photoreceptor cells.
30. The method according to any of claims 27 to 29 wherein the
disease is geographic atrophy.
31. A method of inhibiting HTRA1 protease activity in an eye
comprising administering to a subject in need thereof a
therapeutically effective amount of a compound according to claims
1-25 or a pharmaceutically acceptable salt, solvate, solvate of the
salt or prodrug thereof, or the pharmaceutical composition of claim
26.
Description
BACKGROUND OF THE INVENTION
Field of the Invention
[0001] The present disclosure is directed to novel heterocyclic
prolinamide derivatives, pharmaceutical compositions containing
such novel compounds, as well as methods for preventing and
treating age-related macular degeneration (AMD) and related
diseases of the eye.
Description of the Related Art
[0002] Age-related macular degeneration (AMD) is the leading cause
of severe loss of vision in people over the age of 60. Age is the
major risk factor for the onset of AMD: the likelihood of
developing AMD triples after age 55. Many factors, however,
contribute to the likelihood that an individual will develop
AMD.
[0003] As summarized in WO2001/006262, "environmental" conditions
may modulate the rate at which an individual develops AMD or the
severity of the disease. Light exposure has been proposed as a
possible risk factor, since AMD most severely affects the macula,
where light exposure is high. (See Young, R. W. (1988), Surv.
Ophthalmol. 32(4), 252-69; Taylor, H. R. et al., (1990), Trans.
Amer. Ophthalmol. Soc. 88, 163-73; Schalch W. (1992), Exs, 62,
280-98). The amount of time spent outdoors is associated with
increased risk of choroidal neovascularization in men, and wearing
hats and/or sunglasses is associated with a decreased incidence of
soft drusen (Cruickshanks, K. et al., (1993), Arch. Ophthalmol.,
111, 514-518). Accidental exposure to microwave irradiation has
also been shown to be associated with the development of numerous
drusen (Lim, J. et al., (1993), Retina. 13, 230-3). Cataract
removal and light iris pigmentation has also been reported as a
risk factor in some studies (Sandberg, M. et al., (1994), Invest.
Ophthalmol. Vis. Sci. 35(6), 2734-40). This suggests that: 1) eyes
prone to cataracts may be more likely to develop AMD; 2) the
surgical stress of cataract removal may result in increased risk of
AMD, due to inflammation or other surgically-induced factors; or 3)
cataracts prevent excessive light exposure from falling on the
macula, and are in some way prophylactic for AMD. While it is
possible that dark iris pigmentation may protect the macula from
light damage, it is difficult to distinguish between iris
pigmentation alone and other, co-segregating genetic factors which
may be actual risk factors.
[0004] Smoking, gender (women are at greater risk), obesity, and
repeated exposure to UV radiation also increase the risk of
AMD.
[0005] More recently, a number of HTRA1 single nucleotide
polymorphs (SNP) have been found to be associated with an increased
risk of AMD. See, for example, WO2008/013893A2, WO2008/067040A2 and
WO2008/094370A2. These SNP's include rs11200638, rs10490924,
rs3750848, rs3793917 and rs932275. In particular, the risk allele
rs11200638, was found to be associated with increased HTRA1 mRNA
and protein expression, and HTRA1 is present in drusen in patients
with AMD. (See Dewan et al., (2006), Science 314:989-992; Yang et
al., (2006), Science 314:992-993). These disclosures provide
evidence that HTRA1 is an important factor in AMD and the
progression thereof.
[0006] In broad terms, there are two forms of AMD: dry AMD and wet
AMD. The dry form is the more common, and accounts for 85-90% of
the patients with AMD, and does not typically result in blindness.
In dry AMD, (also called non-neovascular AMD or non-exudative AMD)
drusen appear in the macula of the eye, the cells in the macula
die, and vision becomes blurry. Dry AMD can progress in three
stages: 1) early, 2) intermediate, and 3) advanced dry AMD. Dry AMD
can also progress into wet AMD during any of these stages.
[0007] Wet AMD (also called neovascular or exudative AMD), is
associated with pathologic posterior segment neovascularization.
The posterior segment neovascularization (PSNV) found in exudative
AMD is characterized as pathologic choroidal neovascularization.
Leakage from abnormal blood vessels forming in this process damages
the macula and impairs vision, eventually leading to blindness.
[0008] The end stage of AMD is characterized by a complete
degeneration of the neurosensory retina and of the underlying
retinal pigment epithelium in the macular area. Advanced stages of
AMD can be subdivided into geographic atrophy (GA) and exudative
AMD. Geographic atrophy is characterized by progressive atrophy of
the retinal pigment epithelium (RPE). While GA is typically
considered less severe than the exudative AMD because its onset is
less sudden, to date no treatment has been effective at halting or
slowing its progression.
[0009] Currently, treatment of dry AMD includes the administration
of antioxidant vitamins and/or zinc. For example, one study at the
National Eye Institute assessed a composition comprising vitamin C,
.beta.-carotene, zinc oxide and cupric oxide.
[0010] Treatment of wet AMD is also wanting. Available drug
therapies include: bevacizumab (Avastin.RTM., Genentech, CA),
ranibizumab (Lucentis.RTM., Genentech, CA), pegaptanib
(Macugen.RTM. Bausch & Lomb, NJ), and aflibercept (Eylea.RTM.,
Regeneron, NY). In each instance, the medication is injected into
the eye. Injections may be repeated every four to eight weeks to
maintain the beneficial effect of the medication. Those with a
positive result may partially recover vision as the blood vessels
shrink and the fluid under the retina is absorbed, allowing retinal
cells to regain some function.
[0011] Pharmacologic therapy for the treatment of macular edema
associated with AMD is lacking. The current standard of care is
laser photocoagulation, which is used to stabilize or resolve
macular edema and retard the progression to later stage disease.
Laser photocoagulation may reduce retinal ischemia by destroying
healthy tissue and thereby decreasing metabolic demand; it also may
modulate the expression and production of various cytokine and
trophic factors. There are no current treatments for preventing
loss of vision after dry AMD enters an advanced stage. There are
also no definitive methods for preventing progression of dry AMD to
an advanced stage, other than by avoiding and/or reducing risk
factors and using dietary supplements, which cannot guarantee or be
relied on to stop AMD progression. Thus, there is a need for
therapeutics that can treat dry AMD and prevent progression of dry
to wet AMD.
[0012] The compound
(1-{3-cyclohexyl-2-[naphthalene-2-carbonyl)-amino]-propionyl}-pyrrolidine-
-2-carboxylic acid
[5-(3-cyclohexyl-ureido)-1-dihydroxyboranyl-pentyl]-amide is
disclosed in Grau, S. et. al., (2006), J. Biol. Chem.,
281(10):6124-6129 and in WO2012/078540 (identified therein as
NVP-LB976) as an inhibitor of HTRA1.
[0013] In addition to AMD, a number of publications have described
a potential role of HTRA1 and disease, including retinal
angiomatous proliferation (Ohkuma, Y., et al., (2014) Clin.
Ophthalmol., 8:143-8), foveomacular proliferation (Chowers, I., et
al., (2015) Progress in Retinal and Eye Research, 47:64-85),
musculoskeletal diseases, including osteoarthritis, spinal disk
degeneration rheumatoid arthritis, muscular dystrophy and
osteoporosis (Taiden, A. N. and Richards, P. J. (2013) Am. J.
Pathology, 182(5):1482-8), and treatment of autologous chondrocytes
prior to intraarticular implantation (Ollitrault, D. et al., (2015)
Tissue Engineering, Part C Methods, 21(2):133-47). An HTRA1
inhibitor thus may demonstrate a therapeutic benefit in these
additional indications.
SUMMARY OF THE INVENTION
[0014] The present disclosure is directed to novel heterocyclic
prolinamide derivatives of Formula I, and pharmaceutically
acceptable salts, solvates, solvates of the salts and prodrugs
thereof, pharmaceutical compositions comprising a compound of
Formula I, as well as methods for preventing and treating
age-related macular degeneration (AMD) and related diseases of the
eye comprising administering to a patient in need thereof a
therapeutically effective amount of a compound of Formula I. These
diseases include, but are not limited to, dry-AMD, wet-AMD,
geographic atrophy, diabetic retinopathy, retinopathy of
prematurity, polypoidal choroidal vasculopathy, and degeneration of
retinal or photoreceptor cells. The compounds of the present
disclosure are inhibitors of HTRA1, and are useful in the
prevention and treatment of diseases mediated (in whole or in part)
by HTRA1. The compounds of the present disclosure are also useful
for inhibiting HTRA1 protease activity in an eye or locus of an
arthritis or related condition.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0015] In a first embodiment aspect the present disclosure provides
compounds of Formula (I):
##STR00002##
or a pharmaceutically acceptable salt, solvate, solvate of the salt
or prodrug thereof wherein: W is selected from the group consisting
of: --B(OH).sub.2 and --C(O)C(O)NR.sup.7R.sup.8; X is selected from
the group consisting of: --O--, --S(O).sub.p-- and
--N(C(O)OR.sup.6)--; Y is selected from the group consisting of:
--C(O)--, --SO.sub.2--, and --NHC(O)--; R.sup.1 is selected from
the group consisting of: [0016] (a) --(CH.sub.2).sub.0-6-aryl,
[0017] (b) --(CH.sub.2).sub.0-6-heteroaryl, [0018] (c)
--(CH.sub.2).sub.0-6--C.sub.3-8cycloalkyl optionally substituted
with phenyl, and [0019] (d) --(CH.sub.2).sub.0-6-heterocyclyl
optionally substituted with phenyl or oxo, wherein the aryl and
heteroaryl of choices (a) and (b) are each optionally substituted
with 1 to 3 substituents independently selected from the group
consisting of: [0020] (i) -halogen, [0021] (ii) --CN, [0022] (iii)
--C.sub.1-6alkyl, [0023] (iv) --C.sub.0-6alkyl-R.sup.5, [0024] (v)
--C.sub.2-6alkenyl, [0025] (vi) --C.sub.2-6alkynyl, [0026] (vii)
--C(O)R.sup.7, [0027] (viii) --CO.sub.2R.sup.7, [0028] (ix)
--CONR.sup.7R.sup.8, [0029] (x) --OH, [0030] (xi)
--O--C.sub.1-6alkyl, [0031] (xii) --O--C.sub.0-6alkyl-R.sup.5,
[0032] (xiii) --SH, [0033] (xiv) --S(O).sub.p--C.sub.1-6alkyl,
[0034] (xv) --S(O).sub.p--C.sub.0-6alkyl-R.sup.5, [0035] (xvi)
--S(O).sub.2NR.sup.7R.sup.8, [0036] (xvii) --NO.sub.2, [0037]
(xviii) --NR.sup.7R.sup.8, [0038] (xix) --NHC(O)R.sup.7, [0039]
(xx) --NHC(O)OR.sup.7, [0040] (xxi) --NHC(O)NR.sup.7R.sup.8, [0041]
(xxii) --NHSO.sub.2C.sub.1-6alkyl, and [0042] (xxiii)
--NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group
of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and
(xxiii) is optionally substituted with 1 to 5 substituents
independently selected from -halogen, -haloC.sub.1-4alkyl,
--COR.sup.7, --CO.sub.2R.sup.7, --CONR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; R.sup.2 is selected from the group consisting
of: [0043] (a) --C.sub.3-8alkyl and [0044] (b)
--C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group of
choices (a) and (b) is optionally substituted with 1 to 5
substituents independently selected from: [0045] (i) -halogen,
[0046] (ii) -haloC.sub.1-4alkyl, [0047] (iii) --NR.sup.7R.sup.8,
[0048] (iv) --OH, [0049] (v) --O--C.sub.1-4alkyl, [0050] (vi) --SH,
[0051] (vii) --S--C.sub.1-4alkyl; [0052] (viii)
--NR.sup.7SO.sub.2C.sub.1-4alkyl, and [0053] (ix)
--NR.sup.7C(O)OR.sup.7, R.sup.3a is H, and R.sup.3b is selected
from the group consisting of: [0054] (a) --H, [0055] (b) --OH,
[0056] (c) -heteroaryl, [0057] (d) --O-heteroaryl, [0058] (e)
-heterocycle, [0059] (f) -aryl, and [0060] (g) --O-aryl; wherein
each of the heteroaryl of choices (c) and (d), the heterocycle of
choice (e) and the aryl of choices (f) and (g) is optionally
substituted with 1 to 3 groups independently selected from the
group consisting of: [0061] (i) -halogen, [0062] (ii) --OH, [0063]
(iii) --CR.sup.10R.sup.11R.sup.12, [0064] (iv)
--(CH.sub.2).sub.0-3--NHSO.sub.2--C.sub.1-4alkyl, [0065] (v)
--(CH.sub.2).sub.0-3--SO.sub.2--C.sub.1-4alkyl, [0066] (vi)
--(CH.sub.2).sub.0-3--C(O)O--C.sub.1-4alkyl, and [0067] (vii) --CN;
and wherein the heterocycle of choice (e) is additionally
optionally substituted with 1 to 2 oxo groups; or R.sup.3a and
R.sup.3b together represent oxo; each R.sup.4 is independently
selected from the group consisting of: [0068] (a) --C.sub.1-4alkyl,
[0069] (b) -haloC.sub.1-4alkyl, [0070] (c) --OH, [0071] (d)
--O--C.sub.1-4alkyl, [0072] (e) --O-haloC.sub.1-4alkyl, and [0073]
(f) -halogen; each R.sup.5 is independently selected from the group
consisting of: [0074] (a) --C.sub.3-12cycloalkyl, [0075] (b) -aryl,
[0076] (c) -heteroaryl, and [0077] (d) -heterocyclyl, wherein each
of choices (a) to (d) is optionally substituted with 1 to 3
substituents independently selected from the group consisting of:
[0078] (i) --C.sub.1-4alkyl, [0079] (ii) -halogen, [0080] (iii)
--NR.sup.7R.sup.8, [0081] (iv) --OH, [0082] (v)
--O--C.sub.1-4alkyl, [0083] (vi) --SH, and [0084] (vii)
--S--C.sub.1-4alkyl; wherein each of the alkyl group of choices
(i), (v) and (vii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; R.sup.6 is selected from the group consisting
of: [0085] (a) --C.sub.1-6alkyl, and [0086] (b)
--C.sub.0-6alkyl-aryl; each R.sup.7 and each R.sup.8 are
independently selected from the group consisting of: [0087] (a)
--H, [0088] (b) --C.sub.1-6alkyl, [0089] (c)
--C.sub.0-6alkyl-C.sub.3-12cycloalkyl, [0090] (d)
--C.sub.0-6alkyl-heterocyclyl, [0091] (e)
--C.sub.0-6alkyl-heteroaryl, [0092] (f) --C.sub.0-6alkyl-aryl,
[0093] (g) --C.sub.2-6alkenyl, and [0094] (h) --C.sub.2-6alkynyl,
wherein the alkyl group of choices (b)-(f), the alkenyl group of
choice (g), the cycloalkyl group of choice (c), and the alkynyl
group of (h) is optionally substituted with 1 to 3 groups
independently selected from: [0095] (i) -halogen, [0096] (ii)
--C.sub.1-4alkyl, [0097] (iii) --C(O)C.sub.1-4alkyl, [0098] (iv)
--OH, [0099] (v) --OC.sub.1-4alkyl, [0100] (vi) --SH, [0101] (vii)
--SC.sub.1-4alkyl, [0102] (viii) --NH.sub.2, [0103] (ix)
--NH(C.sub.1-4alkyl), and [0104] (x)
--N(C.sub.1-4alkyl)(C.sub.1-4alkyl); or R.sup.7, R.sup.8 and the
nitrogen atom to which they are attached together form a 3- to
7-membered monocyclic or 6- to 11-membered bicyclic heterocycle
optionally having an additional heteroatom selected from O,
S(O).sub.p, and NR.sup.9, and wherein said heterocycle is
optionally substituted with 1 to 2 groups independently selected
from halogen; R.sup.9 is selected from the group consisting of:
[0105] (a) --H, [0106] (b) --C.sub.1-4alkyl, [0107] (c)
--C(O)--C.sub.1-4alkyl, [0108] (d) --C(O)NH.sub.2, [0109] (e)
--C(O)--NH(C.sub.1-4alkyl), [0110] (f)
--C(O)--N(C.sub.1-4alkyl).sub.2, and [0111] (g)
--C(O)O--C.sub.1-4alkyl; R.sup.10, R.sup.11, and R.sup.12 are
independently selected from the group consisting of: H, halogen,
--OH and --C.sub.1-6 alkyl; or R.sup.10, R.sup.11 and the carbon
atom to which they are attached together form a
C.sub.3-12cycloalkyl or a heterocyclyl group; k is 0, 1, 2, 3 or 4;
n and m are independently selected from 0, 1, 2 and 3, with the
proviso that n+m is 0, 1, 2, 3 or 4; and p is 0, 1 or 2.
[0112] In a second embodiment, for a compound of the first
embodiment, R.sup.1 is selected from the group consisting of:
[0113] (a) -aryl, and [0114] (b) -heteroaryl, wherein the aryl and
heteroaryl of choices (a) and (b) are each optionally substituted
with 1 to 3 substituents independently selected from the group
consisting of: [0115] (i) -halogen, [0116] (ii) --CN, [0117] (iii)
--C.sub.1-6alkyl, [0118] (iv) --C.sub.0-6alkyl-R.sup.5, [0119] (v)
--C.sub.2-6alkenyl, [0120] (vi) --C.sub.2-6alkynyl, [0121] (vii)
--C(O)R.sup.7, [0122] (viii) --CO.sub.2R.sup.7, [0123] (ix)
--CONR.sup.7R.sup.8, [0124] (x) --OH, [0125] (xi)
--O--C.sub.1-6alkyl, [0126] (xii) --O--C.sub.0-6alkyl-R.sup.5,
[0127] (xiii) --SH, [0128] (xiv) --S(O).sub.p--C.sub.1-6alkyl,
[0129] (xv) --S(O).sub.p--C.sub.0-6alkyl-R.sup.5, [0130] (xvi)
--S(O).sub.2NR.sup.7R.sup.8, [0131] (xvii) --NO.sub.2, [0132]
(xviii) --NR.sup.7R.sup.8, [0133] (xix) --NHC(O)R.sup.7, [0134]
(xx) --NHC(O)OR.sup.7, [0135] (xxi) --NHC(O)NR.sup.7R.sup.8, [0136]
(xxii) --NHSO.sub.2C.sub.1-6alkyl, and [0137] (xxiii)
--NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group
of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and
(xxiii) is optionally substituted with 1 to 5 substituents
independently selected from -halogen, -haloC.sub.1-4alkyl,
--COR.sup.7, --CO.sub.2R.sup.7, --CONR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl.
[0138] In a third embodiment, for a compound of any of the
preceding embodiments, R.sup.3b is selected from the group
consisting of: [0139] (a) --OH, [0140] (b) -heteroaryl, [0141] (c)
--O-heteroaryl, [0142] (d) -heterocycle, [0143] (e) -aryl, and
[0144] (f) --O-aryl; wherein each of the heteroaryl of choices (b)
and (c), the heterocycle of choice (d) and the aryl of choices (e)
and (f) is optionally substituted with 1 to 3 groups independently
selected from the group consisting of: [0145] (i) -halogen, [0146]
(ii) --OH, [0147] (iii) --CR.sup.10R.sup.11R.sup.12, [0148] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0149] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0150] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0151] (vii) --CN;
wherein the heterocycle of choice (d) is additionally optionally
substituted with 1 to 2 oxo groups; or R.sup.3a and R.sup.3b
together represent oxo.
[0152] In a fourth embodiment, for a compound of any of the
preceding embodiments, R.sup.3b is selected from the group
consisting of: [0153] (a) --OH, [0154] (b) -heteroaryl, [0155] (c)
--O-heteroaryl, and [0156] (d) -heterocycle, wherein each of the
heteroaryl of choices (b) and (c), and the heterocycle of choice
(d) is optionally substituted with 1 to 3 groups independently
selected from the group consisting of: [0157] (i) -halogen, [0158]
(ii) --OH, [0159] (iii) --CR.sup.10R.sup.11R.sup.12, [0160] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0161] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0162] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0163] (vii) --CN;
wherein the heterocycle of choice (d) is additionally optionally
substituted with 1 to 2 oxo groups.
[0164] In a fifth embodiment, for a compound of any of the
preceding embodiments, R.sup.3b is selected from the group
consisting of: [0165] (a) --OH, [0166] (b)
[0166] ##STR00003## [0167] (c) --O-heteroaryl, and [0168] (d)
##STR00004##
[0168] wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr,
heteroaryl of choice (c), and Hcyl are each optionally substituted
with 1 to 3 groups independently selected from the group consisting
of: [0169] (i) -halogen, [0170] (ii) --OH, [0171] (iii)
--CR.sup.10R.sup.11R.sup.12, [0172] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0173] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0174] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0175] (vii) --CN;
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo
groups.
[0176] In a sixth embodiment, for a compound of any of the
preceding embodiments, R.sup.3b is selected from the group
consisting of: [0177] (a)
##STR00005##
[0177] and [0178] (b)
##STR00006##
[0178] wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr
and Hcyl are each optionally substituted with 1 to 3 groups
independently selected from the group consisting of: [0179] (i)
-halogen, [0180] (ii) --OH, [0181] (iii)
--CR.sup.10R.sup.11R.sup.12, [0182] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0183] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0184] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0185] (vii) --CN;
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo
groups.
[0186] In a seventh embodiment, for a compound of any of the
preceding embodiments, R.sup.2 is --C.sub.1-6alkyl-R.sup.5, wherein
the alkyl group is optionally substituted with 1 to 3 substituents
independently selected from: [0187] (i) -halogen, [0188] (ii)
-haloC.sub.1-4alkyl, [0189] (iii) --O--C.sub.1-4alkyl, [0190] (iv)
--S--C.sub.1-4alkyl.
[0191] In an eighth embodiment, for a compound of any of the
preceding embodiments, R.sup.5 is --C.sub.3-12 cycloalkyl
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of: [0192] (i) --C.sub.1-4alkyl,
[0193] (ii) -halogen, [0194] (iii) --O--C.sub.1-4alkyl, [0195] (iv)
--S--C.sub.1-4alkyl;
[0196] wherein each of the alkyl group of choices (i), (iii) and
(iv) is optionally substituted with 1 to 5 substituents
independently selected from -halogen, -haloC.sub.1-4alkyl, --OH,
--O--C.sub.1-4alkyl, --SH and --S--C.sub.1-4alkyl;
[0197] In a ninth embodiment, for a compound of any of the
preceding embodiments, W is --C(O)C(O)NR.sup.7R.sup.8.
[0198] In a tenth embodiment, for a compound of any of the
preceding embodiments, X is --O-- or --S(O).sub.p--.
[0199] In an eleventh embodiment, the compound of the first
embodiment is a compound having the formula (Ia):
##STR00007##
or a pharmaceutically acceptable salt, solvate, solvate of the salt
or prodrug thereof wherein: W is selected from the group consisting
of: --B(OH).sub.2 and --C(O)C(O)NR.sup.7R.sup.8;
X is --O-- or --S(O).sub.p--;
[0200] Y is selected from the group consisting of: C(O)--,
--SO.sub.2--, and --NHC(O)--; R.sup.1 is selected from the group
consisting of: [0201] (a) -aryl, [0202] (b) -heteroaryl, wherein
the aryl and heteroaryl of choices (a) and (b) are each optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of: [0203] (i) -halogen, [0204] (ii) --CN,
[0205] (iii) --C.sub.1-6alkyl, [0206] (iv)
--C.sub.0-6alkyl-R.sup.5, [0207] (v) --C.sub.2-6alkenyl, [0208]
(vi) --C.sub.2-6alkynyl, [0209] (vii) --C(O)R.sup.7, [0210] (viii)
--CO.sub.2R.sup.7, [0211] (ix) --CONR.sup.7R.sup.8, [0212] (x)
--OH, [0213] (xi) --O--C.sub.1-6alkyl, [0214] (xii)
--O--C.sub.0-6alkyl-R.sup.5, [0215] (xiii) --SH, [0216] (xiv)
--S(O).sub.p--C.sub.1-6alkyl, [0217] (xv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, [0218] (xvi)
--S(O).sub.2NR.sup.7R.sup.8, [0219] (xvii) --NO.sub.2, [0220]
(xviii) --NR.sup.7R.sup.8, [0221] (xix) --NHC(O)R.sup.7, [0222]
(xx) --NHC(O)OR.sup.7, [0223] (xxi) --NHC(O)NR.sup.7R.sup.8, [0224]
(xxii) --NHSO.sub.2C.sub.1-6alkyl, and [0225] (xxiii)
--NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group
of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and
(xxiii) is optionally substituted with 1 to 5 substituents
independently selected from -halogen, -haloC.sub.1-4alkyl,
--COR.sup.7, --CO.sub.2R.sup.7, --CONR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; R.sup.3a is H and R.sup.3b is selected from
the group consisting of: [0226] (a) --OH, [0227] (b) -heteroaryl,
[0228] (c) --O-heteroaryl, [0229] (d) -heterocycle, [0230] (e)
-aryl, and [0231] (f) --O-aryl; wherein each of the heteroaryl of
choices (b) and (c), the heterocycle of choice (d) and the aryl of
choices (e) and (f) is optionally substituted with 1 to 3 groups
independently selected from the group consisting of: [0232] (i)
-halogen, [0233] (ii) --OH, [0234] (iii)
--CR.sup.10R.sup.11R.sup.12, [0235] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0236] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0237] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0238] (vii) --CN;
wherein the heterocycle of choice (d) is additionally optionally
substituted with 1 to 2 oxo groups; or R.sup.3a and R.sup.3b
together represent oxo; R.sup.4 is selected from the group
consisting of: [0239] (a) --C.sub.1-4alkyl, [0240] (b)
-haloC.sub.1-4alkyl, [0241] (c) --OH, [0242] (d)
--O--C.sub.1-4alkyl, [0243] (e) --O-haloC.sub.1-4alkyl, and [0244]
(f) -halogen; R.sup.5 is --C.sub.3-12cycloalkyl optionally
substituted with 1 to 3 substituents independently selected from
the group consisting of: [0245] (i) --C.sub.1-4alkyl, [0246] (ii)
-halogen, [0247] (iii) --O--C.sub.1-4alkyl, [0248] (iv)
--S--C.sub.1-4alkyl; wherein each of the alkyl group of choices
(i), (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; each R.sup.7 and each R.sup.8 are
independently selected from the group consisting of: [0249] (a)
--H, [0250] (b) --C.sub.1-6alkyl, [0251] (c)
--C.sub.0-6alkyl-C.sub.3-12cycloalkyl, [0252] (d)
--C.sub.0-6alkyl-heterocyclyl, [0253] (e)
--C.sub.0-6alkyl-heteroaryl, [0254] (f) --C.sub.0-6alkyl-aryl,
[0255] (g) --C.sub.2-6alkenyl, and [0256] (h) --C.sub.2-6alkynyl,
wherein the alkyl group of choices (b)-(f), the alkenyl group of
choice (g), the cycloalkyl group of choice (c), and the alkynyl
group of (h) is optionally substituted with 1 to 3 groups
independently selected from: [0257] (i) -halogen, [0258] (ii)
--C.sub.1-4alkyl, [0259] (iii) --C(O)C.sub.1-4alkyl, [0260] (iv)
--OH, [0261] (v) --OC.sub.1-4alkyl, [0262] (vi) --SH, [0263] (vii)
--SC.sub.1-4alkyl, [0264] (viii) --NH.sub.2, [0265] (ix)
--NH(C.sub.1-4alkyl), and [0266] (x)
--N(C.sub.1-4alkyl)(C.sub.1-4alkyl); or R.sup.7, R.sup.8 and the
nitrogen atom to which they are attached together form a 3- to
7-membered monocyclic or 6- to 11-membered bicyclic heterocycle
optionally having an additional heteroatom selected from O,
S(O).sub.p, and NR.sup.9, and wherein said heterocycle is
optionally substituted with 1 to 2 groups independently selected
from halogen; R.sup.9 is selected from the group consisting of:
[0267] (a) --H, [0268] (b) --C.sub.1-4alkyl, [0269] (c)
--C(O)--C.sub.1-4alkyl, [0270] (d) --C(O)NH.sub.2, [0271] (e)
--C(O)--NH(C.sub.1-4alkyl), [0272] (f)
--C(O)--N(C.sub.1-4alkyl).sub.2, and [0273] (g)
--C(O)O--C.sub.1-4alkyl; R.sup.10, R.sup.11, and R.sup.12 are
independently selected from the group consisting of: H, halogen,
--OH and --C.sub.1-6 alkyl; or R.sup.10, R.sup.11 and the atom to
which they are attached together form a C.sub.3-12cycloalkyl or a
heterocyclyl group; k is 0, 1, 2, 3 or 4; n and m are independently
selected from 0, 1, 2 and 3, with the proviso that n+m is 0, 1, 2,
3 or 4; p is 0, 1 or 2.
[0274] In a twelfth embodiment, for a compound of the eleventh
embodiment having formula (Ia), R.sup.3b is selected from the group
consisting of: [0275] (a) --OH, [0276] (b)
[0276] ##STR00008## [0277] (c) --O-heteroaryl, and [0278] (d)
##STR00009##
[0278] wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr,
heteroaryl of choice (c), and Hcyl are each optionally substituted
with 1 to 3 groups independently selected from the group consisting
of: [0279] (i) -halogen, [0280] (ii) --OH, [0281] (iii)
--CR.sup.10R.sup.11R.sup.12, [0282] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0283] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0284] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0285] (vii) --CN;
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo
groups.
[0286] In a thirteenth embodiment, for a compound having the
formula (Ia) of any of the preceding embodiments, R.sup.3b is
selected from the group consisting of: [0287] (a)
##STR00010##
[0287] and [0288] (b)
##STR00011##
[0288] wherein HAr is heteroaryl and Hcyl is heterocycle, and HAr
and Hcyl are each optionally substituted with 1 to 3 groups
independently selected from the group consisting of: [0289] (i)
-halogen, [0290] (ii) --OH, [0291] (iii)
--CR.sup.10R.sup.11R.sup.12, [0292] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0293] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0294] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0295] (vii) --CN;
wherein Hcyl is additionally substituted with 1 to 2 oxo
groups.
[0296] In a fourteenth embodiment, for a compound having the
formula (Ia) of any of the preceding embodiments, W is
--C(O)C(O)NH.sub.2.
[0297] In a fifteenth embodiment, for a compound having the formula
(Ia) of any of the preceding embodiments, Y is --C(O)--.
[0298] In a sixteenth embodiment, for a compound having the formula
(Ia) of any of the preceding embodiments,
W is --C(O)C(O)NH.sub.2;
Y is --C(O)--; and
[0299] R.sup.3b is selected from the group consisting of: [0300]
(a)
##STR00012##
[0300] and [0301] (b)
##STR00013##
[0301] wherein HAr is heteroaryl and Hcyl is heterocycle, and each
heteroaryl and heterocycle is optionally substituted with 1 to 3
groups independently selected from the group consisting of: [0302]
(i) -halogen, [0303] (ii) --OH, [0304] (iii)
--C.sup.10R.sup.11R.sup.12, [0305] (iv)
--C.sub.0-3alkyl-NHSO.sub.2--C.sub.1-4alkyl, [0306] (v)
--C.sub.0-3alkyl-SO.sub.2--C.sub.1-4alkyl, [0307] (vi)
--C.sub.0-3alkyl-C(O)O--C.sub.1-4alkyl, and [0308] (vii) --CN;
wherein the heterocycle is additionally substituted with 1 to 2 oxo
groups
[0309] In a seventeenth embodiment, the compound of the first
embodiment is a compound having the formula (Ib):
##STR00014##
or a pharmaceutically acceptable salt, solvate, solvate of the salt
or prodrug thereof, wherein W is selected from the group consisting
of: --B(OH).sub.2 and --C(O)C(O)NR.sup.7R.sup.8; X is selected from
the group consisting of: --O--, --S(O).sub.p-- and
--N(C(O)OR.sup.6)--; Y is selected from the group consisting of:
--C(O)--, --SO.sub.2--, and --NHC(O)--; R.sup.1 is selected from
the group consisting of: [0310] (a) -aryl, [0311] (b) -heteroaryl,
wherein the aryl and heteroaryl of choices (a) and (b) are each
optionally substituted with 1 to 3 substituents independently
selected from the group consisting of: [0312] (i) -halogen, [0313]
(ii) --CN, [0314] (iii) --C.sub.1-6alkyl, [0315] (iv)
--C.sub.0-6alkyl-R.sup.5, [0316] (v) --C.sub.2-6alkenyl, [0317]
(vi) --C.sub.2-6alkynyl, [0318] (vii) --C(O)R.sup.7, [0319] (viii)
--CO.sub.2R.sup.7, [0320] (ix) --CONR.sup.7R.sup.8, [0321] (x)
--OH, [0322] (xi) --O--C.sub.1-6alkyl, [0323] (xii)
--O--C.sub.0-6alkyl-R.sup.5, [0324] (xiii) --SH, [0325] (xiv)
--S(O).sub.p--C.sub.1-6alkyl, [0326] (xv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, [0327] (xvi)
--S(O).sub.2NR.sup.7R.sup.8, [0328] (xvii) --NO.sub.2, [0329]
(xviii) --NR.sup.7R.sup.8, [0330] (xix) --NHC(O)R.sup.7, [0331]
(xx) --NHC(O)OR.sup.7, [0332] (xxi) --NHC(O)NR.sup.7R.sup.8, [0333]
(xxii) --NHSO.sub.2C.sub.1-6alkyl, and [0334] (xxiii)
--NHSO.sub.2C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group
of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii) and
(xxiii) is optionally substituted with 1 to 5 substituents
independently selected from -halogen, -haloC.sub.1-4alkyl,
--COR.sup.7, --CO.sub.2R.sup.7, --CONR.sup.7R.sup.8,
--NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; R.sup.2 is selected from the group consisting
of: [0335] (a) --C.sub.3-8alkyl and [0336] (b)
--C.sub.0-6alkyl-R.sup.5, wherein each of the alkyl group of
choices (a) and (b) is optionally substituted with 1 to 5
substituents independently selected from: [0337] (i) -halogen,
[0338] (ii) -haloC.sub.1-4alkyl, [0339] (iii) --NR.sup.7R.sup.8,
[0340] (iv) --OH, [0341] (v) --O--C.sub.1-4alkyl, [0342] (vi) --SH,
[0343] (vii) --S--C.sub.1-4alkyl; [0344] (viii)
--NR.sup.7SO.sub.2C.sub.1-4alkyl, and [0345] (ix)
--NR.sup.7C(O)OR.sup.7, R.sup.4 is selected from the group
consisting of: [0346] (a) --C.sub.1-4alkyl, [0347] (b)
-haloC.sub.1-4alkyl, [0348] (c) --OH, [0349] (d)
--O--C.sub.1-4alkyl, [0350] (e) --O-haloC.sub.1-4alkyl, and [0351]
(f) -halogen; R.sup.5 is selected from the group consisting of:
[0352] (a) --C.sub.3-12cycloalkyl, [0353] (b) -aryl, [0354] (c)
-heteroaryl, and [0355] (d) -heterocyclyl, wherein each of choices
(a) to (d) is optionally substituted with 1 to 3 substituents
independently selected from the group consisting of: [0356] (i)
--C.sub.1-4alkyl, [0357] (ii) -halogen, [0358] (iii)
--NR.sup.7R.sup.8, [0359] (iv) --OH, [0360] (v)
--O--C.sub.1-4alkyl, [0361] (vi) --SH, and [0362] (vii)
--S--C.sub.1-4alkyl; wherein each of the alkyl group of choices
(i), (v) and (vii) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl; R.sup.6 is selected from the group consisting
of: [0363] (a) --C.sub.1-6alkyl, and [0364] (b)
--C.sub.0-6alkyl-aryl; each R.sup.7 and each R.sup.8 are
independently selected from the group consisting of: [0365] (a)
--H, [0366] (b) --C.sub.1-6alkyl, [0367] (c)
--C.sub.0-6alkyl-C.sub.3-12cycloalkyl, [0368] (d)
--C.sub.0-6alkyl-heterocyclyl, [0369] (e)
--C.sub.0-6alkyl-heteroaryl, [0370] (f) --C.sub.0-6alkyl-aryl,
[0371] (g) --C.sub.2-6alkenyl, and [0372] (h) --C.sub.2-6alkynyl,
wherein the alkyl group of choices (b)-(f), the alkenyl group of
choice (g), the cycloalkyl group of choice (c), and the alkynyl
group of (h) is optionally substituted with 1 to 3 groups
independently selected from: [0373] (i) -halogen, [0374] (ii)
--C.sub.1-4alkyl, [0375] (iii) --C(O)C.sub.1-4alkyl, [0376] (iv)
--OH, [0377] (v) --OC.sub.1-4alkyl, [0378] (vi) --SH, [0379] (vii)
--SC.sub.1-4alkyl, [0380] (viii) --NH.sub.2, [0381] (ix)
--NH(C.sub.1-4alkyl), and [0382] (x)
--N(C.sub.1-4alkyl)(C.sub.1-4alkyl); or R.sup.7, R.sup.8 and the
nitrogen atom to which they are attached together form a 3- to
7-membered monocyclic or 6- to 11-membered bicyclic heterocycle
optionally having an additional heteroatom selected from O,
S(O).sub.p, and NR.sup.9, and wherein said heterocycle is
optionally substituted with 1 to 2 groups independently selected
from halogen; R.sup.9 is selected from the group consisting of:
[0383] (a) --H, [0384] (b) --C.sub.1-4alkyl, [0385] (c)
--C(O)--C.sub.1-4alkyl, [0386] (d) --C(O)NH.sub.2, [0387] (e)
--C(O)--NH(C.sub.1-4alkyl), [0388] (f)
--C(O)--N(C.sub.1-4alkyl).sub.2, and [0389] (g)
--C(O)O--C.sub.1-4alkyl; R.sup.10, R.sup.11, and R.sup.12 are
independently selected from the group consisting of: H, halogen,
--OH and --C.sub.1-6alkyl; or R.sup.10, R.sup.11 and the carbon
atom to which they are attached together form a
C.sub.3-12cycloalkyl or a heterocyclyl group; k is 0, 1, 2, 3 or 4;
n and m are independently selected from 0, 1, 2 and 3, with the
proviso that n+m is 0, 1, 2, 3 or 4; p is 0, 1 or 2.
[0390] In an eighteenth embodiment, for a compound of the
seventeenth embodiment,
R.sup.2 is --C.sub.1-3alkyl-R.sup.5, and R.sup.5 is
--C.sub.3-12cycloalkyl, optionally substituted with 1 to 3
substituents independently selected from the group consisting of:
[0391] (i) --C.sub.1-4alkyl, [0392] (ii) -halogen, [0393] (iii)
--O--C.sub.1-4alkyl, [0394] (iv) --S--C.sub.1-4alkyl; wherein each
of the alkyl group of choices (i), (iii) and (iv) is optionally
substituted with 1 to 5 substituents independently selected from
-halogen, -haloC.sub.1-4alkyl, --OH, --O--C.sub.1-4alkyl, --SH and
--S--C.sub.1-4alkyl.
[0395] In a nineteenth embodiment, for a compound having the
formula (Ib) of any of the preceding embodiments,
W is --C(O)C(O)NH.sub.2;
X is --O-- or --S(O).sub.p--; and
Y is --C(O)--.
[0396] In a twentieth embodiment, for a compound of any of the
preceding embodiments, R.sup.1 is selected from the group
consisting of: [0397] (a) phenyl, [0398] (b) naphthyl, [0399] (c)
5- or 6-membered monocyclic heteroaryl ring, said ring having a
heteroatom selected from N, O and S, and optionally 1, 2 or 3
additional N atoms; and [0400] (d) 8-, 9-, or 10-membered fused
bicyclic heteroaryl ring, said ring having a heteroatom selected
from N, O and S, and optionally 1, 2 or 3 additional N atoms;
wherein each of choices (a)-(d) is optionally substituted with 1 or
2 substituents independently selected from the group consisting of:
[0401] (i) -halogen, [0402] (ii) --CONR.sup.7R.sup.8, [0403] (iii)
--S(O).sub.p--C.sub.1-6alkyl, [0404] (iv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, [0405] (v)
--S(O).sub.2NR.sup.7R.sup.8, wherein each of the alkyl group of
choices (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl.
[0406] In a twenty-first embodiment, for a compound of any of the
preceding embodiments, n and m are each 1, and k is 0.
[0407] In a twenty-second embodiment, the compound of the first
embodiment is a compound having the formula (Ic):
##STR00015##
or a pharmaceutically acceptable salt, solvate, solvate of the salt
or prodrug thereof, wherein
X is O or S(O).sub.n;
[0408] R.sup.1 is selected from the group consisting of: [0409] (a)
phenyl, [0410] (b) naphthyl, [0411] (c) 5- or 6-membered monocyclic
heteroaryl ring, said ring having a heteroatom selected from N, O
and S, and optionally 1, 2 or 3 additional N atoms; and [0412] (d)
8-, 9-, or 10-membered fused bicyclic heteroaryl ring, said ring
having a heteroatom selected from N, O and S, and optionally 1, 2
or 3 additional N atoms; wherein each of choices (a)-(d) is
optionally substituted with 1 or 2 substituents independently
selected from the group consisting of: [0413] (i) -halogen, [0414]
(ii) --CONR.sup.7R.sup.8, [0415] (iii)
--S(O).sub.p--C.sub.1-6alkyl, [0416] (iv)
--S(O).sub.p--C.sub.0-6alkyl-R.sup.5, [0417] (v)
--S(O).sub.2NR.sup.7R.sup.8, wherein each of the alkyl group of
choices (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl.
[0418] In a twenty-third embodiment, for a compound of the
twenty-second embodiment, R.sup.1 is selected from naphthyl,
imidazo[1,2-a]pyridinyl, quinolinyl, indazolyl, benzotriazolyl,
benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzofuranyl, indolyl,
benzimidazolyl, and isoquinolinone.
[0419] In a twenty-fourth embodiment, for a compound of the
twenty-second embodiment, R.sup.1 is phenyl optionally substituted
with 1 or 2 substituents independently selected from the group
consisting of: [0420] (i) -halogen, [0421] (ii)
--CONR.sup.7R.sup.8, [0422] (iii) --S(O).sub.p--C.sub.1-6alkyl,
[0423] (iv) --S(O).sub.p--C.sub.0-6alkyl-R.sup.5, [0424] (v)
--S(O).sub.2NR.sup.7R.sup.8, wherein each of the alkyl group of
choices (iii) and (iv) is optionally substituted with 1 to 5
substituents independently selected from -halogen,
-haloC.sub.1-4alkyl, --COR.sup.7, --CO.sub.2R.sup.7,
--CONR.sup.7R.sup.8, --NR.sup.7R.sup.8, --OH, --O--C.sub.1-4alkyl,
--SH and --S--C.sub.1-4alkyl.
[0425] In a twenty-fifth embodiment, the compound of the first
embodiment is selected from the group consisting of: [0426]
tert-butyl
4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino--
2-oxoacetyl)piperidine-1-carboxylate; [0427]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tr-
iazol-1-yl)pyrrolidine-2-carboxamide; [0428]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0429]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0430]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide;
[0431]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-2-(4-cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0432]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamide; [0433]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carboxamide; [0434]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0435]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0436]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4--
((2-amino-2-oxoethyl)sulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0437]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0438]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(1-methoxy-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0439]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(difluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0440]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(trifluoromethoxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0441]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzamido)propan-
oyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbo-
xamide; [0442]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(2-hydroxypropan-2-yl)benzamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0443]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(2,2,2-trifluoro-1,1-dihydroxyethyl)benzamido)propanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0444]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((2-
R)-3-cyclohexyl-2-(4-(2,2,2-trifluoro-1-hydroxyethyl)benzamido)propanoyl)--
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamid-
e; [0445]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyra-
n-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrol-
idin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]isoxazole-3-carboxamide;
[0446]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran--
4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolid-
in-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]oxazole-2-carboxamide;
[0447]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran--
4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolid-
in-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)benzo[d]thiazole-2-carboxamide;
[0448]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-2-(benzofuran-5-carboxamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0449]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-6-carboxamide; [0450]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indole-2-carboxamide; [0451]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-fluorobenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2-
,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0452]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(3-hydroxyoxetan-3-yl)benzamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0453]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0454]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0455]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H1-pyran-4-yl)c-
arbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-y-
l)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide; [0456]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)ca-
rbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl-
)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-6-carboxamide;
[0457]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran--
4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolid-
in-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-2-carboxamide-
; [0458]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-
-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrroli-
din-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d]imidazole-6-carboxamid-
e; [0459]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-(-
(R)-3-cyclohexyl-2-(3-fluoro-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(-
2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0460]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-3-cyclohexyl-2-(3-methyl-4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2--
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0461]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-3-cyclohexyl-2-(4-(cyclopentylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydr-
oxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0462]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-y-
l)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0463]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((trifluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0464]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-((2,2-difluoroethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hyd-
roxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0465]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0466]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-sulfamoylbenzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H--
1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0467]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0468]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxy-
propan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0469]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N,N-diethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0470]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0471]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0472]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(2-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0473]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4--
(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0474]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(4--
(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0475]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0476]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-3-cyclohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0477]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-3-cyclohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-
-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide-
; [0478]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((-
R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoyl)--
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamid-
e; [0479]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-(-
(R)-3-cyclohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0480]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan--
2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0481]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(-
5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0482]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R-
)-3-cyclohexyl-2-(3-phenylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-
-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0483]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0484]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(4-(trifluoromethyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0485]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(1-methyl-1H-indol-4-yl)ureido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0486]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3--
(3-chloro-4-fluorophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0487]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-cyclohexylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,-
2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0488]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(naphthalen-1-yl)ureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0489]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(4-phenyltetrahydro-2H-pyran-4-yl)ureido)propanoyl)-4-(5-(2-h-
ydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0490]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3--
benzylureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3--
triazol-1-yl)pyrrolidine-2-carboxamide; [0491]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-(3--
(4-cyanophenyl)ureido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0492]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-(4-(methylsulfonyl)phenyl)ureido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0493]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0494]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3,4-difluorophenylsulfonamido)propanoyl)-4-(5-(2-hydroxypropan--
2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0495]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(difluoromethoxy)phenylsulfonamido)propanoyl)-4-(5-(2-hydroxy-
propan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0496]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-am-
ino-2-oxoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-
-triazol-1-yl)pyrrolidine-2-carboxamide; [0497]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)py-
rrolidine-2-carboxamide; [0498]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N--((R)-4-(2-amin-
o-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1--
yl)pyrrolidine-2-carboxamide; [0499]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N--((S)-4-(2-amin-
o-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1--
yl)pyrrolidine-2-carboxamide; [0500]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,-
3-triazol-1-yl)pyrrolidine-2-carboxamide; [0501]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0502]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropa-
n-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0503]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)picolinamide; [0504]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(ethylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0505]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)imidazo[1,2-a]pyridine-6-carboxamide;
[0506]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopy-
ran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrr-
olidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-oxo-1,2-dihydroisoquinoline--
3-carboxamide; [0507]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxy-
propan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0508]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydr-
oxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0509]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-2-methyl-2H-benzo[d][1,2,3]triazole-5-
-carboxamide; [0510]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-6-
-carboxamide; [0511]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-5-
-carboxamide; [0512]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((2-methoxyethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0513]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-benzo[d][1,2,3]triazole-5-carboxam-
ide; [0514]
N.sup.1--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyr-
an-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrro-
lidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalamide; [0515]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-
-benzamido-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tri-
azol-1-yl)pyrrolidine-2-carboxamide; [0516]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-y-
l)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin--
1-yl)-3-cyclohexyl-1-oxopropan-2-yl)isonicotinamide; [0517]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(prop-2-yn-1-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-
-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0518]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-3-cyclohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)pro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide; [0519]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(oxetan-3-yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0520]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(morpholinosulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxyp-
ropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0521]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-methylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0522]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N,N-dimethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0523]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypro-
pan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0524]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(isopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0525]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((cyclopropylmethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-
-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0526]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)propanoy-
l)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxa-
mide; [0527]
(2S,4S)-1-((R)-2-(4-((4-acetylpiperazin-1-yl)sulfonyl)benzamido)-3-cycloh-
exylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(-
5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0528]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-3-cyclohexyl-2-(4-(pyrrolidine-1-carbonyl)benzamido)propanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0529]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-2-(4-(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-h-
ydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0530]
N.sup.1--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyr-
an-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrro-
lidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-N.sup.4,N.sup.4-dimethylterepht-
halamide; [0531]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(1-methylcyclopropyl)sulfamoyl)benzamido)propanoyl)-4--
(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0532]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-3-cyclohexyl-2-(4-((4-methylpiperazin-1-yl)sulfonyl)benzamido)propan-
oyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbo-
xamide; [0533]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-
-(4-(azetidin-1-ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0534]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(2-hyd-
roxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0535]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(cyclopropylmethyl)sulfamoyl)benzamido)propanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0536]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(-
2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0537]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-
-((R)-3-cyclohexyl-2-(4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamido)propa-
noyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carb-
oxamide; [0538]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(tetrahydro-2H-thiopyran-4-yl)sulfamoyl)benzamido)prop-
anoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-car-
boxamide; [0539]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)propanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de; [0540]
(2S,4S)-1-((R)-2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-ylsulfonyl)b-
enzamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-t-
hiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidi-
ne-2-carboxamide; [0541]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-(N-(3,3-dimethyl-2-oxobutyl)sulfamoyl)benzamido)propanoyl-
)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxam-
ide; [0542]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de; [0543]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-
-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0544]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2--
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0545]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiop-
yran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)pr-
opanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-c-
arboxamide; [0546]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)quinoline-3-carboxamide;
[0547]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahyd-
ro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triaz-
ol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-7-carb-
oxamide; [0548]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-(4-cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0549]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1H-indazole-6-carboxamide-
; [0550]
N.sup.1--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidot-
etrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,-
3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)terephthalam-
ide; [0551]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-nitrobenzamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0552]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-(4-bromobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0553]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-(4-chloro-2,5-difluorobenzamido)-3-cyclohexylpropanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0554]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiop-
yran-4-yl)-1-((R)-3-cyclohexyl-2-(3,4-dichlorobenzamido)propanoyl)-4-(5-(2-
-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0555]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahyd-
ro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triaz-
ol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-6-hydroxynicotinam-
ide; [0556]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-hydroxyisoquinoline-3-c-
arboxamide; [0557]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-fluoroquinoline-3-carbo-
xamide; [0558]
N--((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-t-
hiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl-
)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-chloroquinoline-3-carbo-
xamide; [0559]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)--
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamid-
e; [0560]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thi-
opyran-4-yl)-1-((R)-2-(4-(N-cyclobutylsulfamoyl)benzamido)-3-cyclohexylpro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide; [0561]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-(spiro[3.3]heptan-2-yl)sulfamoyl)benzamido-
)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine--
2-carboxamide; [0562]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-(2,2-difluoroethyl)sulfamoyl)benzamido)pro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide; [0563]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)--
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamid-
e;
[0564]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiop-
yran-4-yl)-1-((R)-2-(4-(N-(tert-butyl)sulfamoyl)benzamido)-3-cyclohexylpro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide; [0565]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-phenylsulfamoyl)benzamido)propanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0566]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiop-
yran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-methylsulfamoyl)benza-
mido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolid-
ine-2-carboxamide; [0567]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopropyl-N-ethylsulfamoyl)benzamido)pro-
panoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-ca-
rboxamide; [0568]
(2S,4R)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N-cyclopentylsulfamoyl)benzamido)propanoyl)--
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamid-
e; [0569]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thi-
opyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamid-
o)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-
-2-carboxamide; [0570]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0571]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0572]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0573]
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)--
1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4--
(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
[0574]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-am-
ino-2-oxoacetyl)tetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,-
2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0575]
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1-oxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1-
,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0576]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0577]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-
-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0578]
(2S,4S)--N--((R)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-
-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0579]
(2S,4S)--N--((S)-4-((2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-
-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-
-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0580]
(2S,4S)--N--((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0581]
(2S,4S)--N--((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0582]
(2S,4S)--N--((R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0583]
(2S,4S)--N--((S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl--
2-(4-(N-cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; [0584]
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide;
[0585]
(S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino--
2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-oxopyrrolidine-2-carboxamide;
[0586]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-am-
ino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2,4-dioxo-3,4-dihydropyrimidi-
n-1(2H)-yl)pyrrolidine-2-carboxamide; [0587]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(6-oxopyridazin-1(6H)-yl)pyrrolidine--
2-carboxamide; [0588]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-oxo-[1,2,4]triazolo[4,3-a]pyridin--
2(3H)-yl)pyrrolidine-2-carboxamide; [0589]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(1,3-dioxoisoindolin-2-yl)pyrrolidine-
-2-carboxamide; [0590]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-((5-methylisoxazol-3-yl)oxy)pyrrolidi-
ne-2-carboxamide; [0591]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-chloro-6-oxopyridazin-1(6H)-yl)pyr-
rolidine-2-carboxamide; [0592]
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2-oxopyridin-1(2H)-yl)pyrrolidine-2--
carboxamide; and [0593]
(4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro--
2H-pyran-4-yl)boronic acid; or a pharmaceutically acceptable salt,
solvate, salt of the solvate, or prodrug thereof.
[0594] In a twenty-sixth embodiment, the present disclosure
provides a pharmaceutical composition comprising a compound of any
of the first through the twenty-fifth embodiments, and a
pharmaceutically acceptable carrier.
[0595] In a twenty-seventh embodiment, the present disclosure
provides a method of preventing, or treating a disease of the eye
selected from dry-AMD, wet-AMD, geographic atrophy, diabetic
retinopathy, retinopathy of prematurity, polypoidal choroidal
vasculopathy, and degeneration of retinal or photoreceptor cells,
comprising: administering to a subject in need thereof a
therapeutically effective amount of a compound according to any of
the first through twenty-fifth embodiments, or a pharmaceutically
acceptable salt, solvate, solvate of the salt or prodrug thereof,
or the pharmaceutical composition of the twenty-sixth
embodiment.
[0596] In a twenty-eighth embodiment, for the method of the
twenty-seventh embodiment, the method of prevention is selected
from delaying the onset of disease and reducing the risk of
developing a disease of the eye, wherein the disease of the eye is
selected from dry-AMD, wet-AMD, geographic atrophy, diabetic
retinopathy, retinopathy of prematurity, polypoidal choroidal
vasculopathy, and degeneration of retinal or photoreceptor
cells.
[0597] In a twenty-ninth embodiment, for the method of the
twenty-seventh embodiment the method of treating a disease of the
eye is selected from controlling, alleviating, and slowing the
progression of, wherein the disease is selected from dry-AMD,
wet-AMD, geographic atrophy, diabetic retinopathy, retinopathy of
prematurity, polypoidal choroidal vasculopathy, and degeneration of
retinal or photoreceptor cells.
[0598] In a thirtieth embodiment, for the method of any one of the
twenty-seventh through the twenty-ninth embodiments, the disease is
geographic atrophy.
[0599] In a thirty-first embodiment, the present disclosure
provides a method of inhibiting HtrAl protease activity in an eye,
comprising administering to a subject in need thereof a
therapeutically effective amount of any one of the compounds of the
first through twenty-fifth embodiments or a pharmaceutically
acceptable salt, solvate, solvate of the salt or prodrug thereof,
or the pharmaceutical composition of the twenty-sixth
embodiment.
[0600] Any of the features of an embodiment is applicable to all
embodiments identified herein. Moreover, any of the features of an
embodiment is independently combinable, partly or wholly with other
embodiments described herein in any way, e.g., one, two, or three
or more embodiments may be combinable in whole or in part. Further,
any of the features of an embodiment may be made optional to other
embodiments. Any embodiment of a method can comprise another
embodiment of a compound, and any embodiment of a compound can be
configured to perform a method of another embodiment.
Definitions
[0601] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of ordinary skill in the art. All patents, applications, published
applications and other publications referenced herein are
incorporated by reference in their entirety unless stated
otherwise. In the event that there are a plurality of definitions
for a term herein, those in this section prevail unless stated
otherwise.
[0602] The term "patient" includes mammals such as mice, rats,
cows, sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and
humans.
[0603] The term "halo" or "halogen" refers to any radical of
fluorine, chlorine, bromine or iodine.
[0604] The term "alkyl" refers to a saturated hydrocarbon chain
that may be a straight chain or branched chain, containing the
indicated number of carbon atoms. For example, C.sub.1-6alkyl
indicates that the group may have from 1 to 6 (inclusive) carbon
atoms in it. In some embodiments, an alkyl is a C.sub.1-6alkyl
which represents a straight-chain or branched saturated hydrocarbon
radical having 1 to 6 carbon atoms. Examples of alkyl include
without limitation methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, and tert-butyl. The notation "C.sub.0-nalkyl"
indicates the absence of an alkyl moiety, or the presence of an
alkyl moiety having 1 to n carbon atoms. Thus, for example, the
term "C.sub.0-6alkyl-R.sup.5" indicates that the R.sup.5 group is
attached directly to the parent moiety, or that there is an
intervening alkyl group of 1 to 6 carbon atoms between R.sup.5 and
the parent moiety; such an intervening group may be, for example,
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH(CH.sub.3)-- and
--C(CH.sub.3).sub.2--.
[0605] The term "haloalkyl" refers to an alkyl group in which at
least one hydrogen atom is replaced by halo. In some embodiments,
more than one hydrogen atom (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, or 14) are replaced by halo. In these embodiments, the
hydrogen atoms can each be replaced by the same halogen (e.g.,
fluoro) or the hydrogen atoms can be replaced by a combination of
different halogens (e.g., fluoro and chloro). "Haloalkyl" also
includes alkyl moieties in which all hydrogens have been replaced
by halo (sometimes referred to herein as perhaloalkyl, e.g.,
perfluoroalkyl, such as trifluoromethyl).
[0606] As referred to herein, the term "alkoxy" refers to a group
of formula --O-(alkyl). Alkoxy can be, for example, methoxy,
ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy,
pentoxy, 2-pentoxy, 3-pentoxy, or hexyloxy. Likewise, the term
"thioalkoxy" refers to a group of formula --S-(alkyl). The terms
"haloalkoxy" and "thiohaloalkoxy" refer to --O-(haloalkyl) and
--S-(haloalkyl), respectively. The term "sulfhydryl" refers to
--SH.
[0607] The term "aralkyl" refers to an alkyl moiety in which an
alkyl hydrogen atom is replaced by an aryl group. One of the
carbons of the alkyl moiety serves as the point of attachment of
the aralkyl group to another moiety. Non-limiting examples of
"aralkyl" include benzyl, 2-phenylethyl, and 3-phenylpropyl
groups.
[0608] The term "alkenyl" refers to a straight or branched
hydrocarbon chain containing the indicated number of carbon atoms
and having one or more carbon-carbon double bonds. Alkenyl groups
can include, e.g., vinyl, allyl, 1-butenyl, and 2-hexenyl. In some
embodiments, an alkenyl is a C.sub.2-6alkenyl.
[0609] The term "alkynyl" refers to a straight or branched
hydrocarbon chain containing the indicated number of carbon atoms
and having one or more carbon-carbon triple bonds. Alkynyl groups
can include, e.g., ethynyl, propargyl, 1-butynyl, and 2-hexynyl. In
some embodiments, an alkynyl is a C.sub.2-6alkynyl.
[0610] The term "heterocycle", "heterocyclyl" or "heterocyclic" as
used herein except where noted, represents a stable 4-, 5-, 6- or
7-membered monocyclic- or a stable 6-, 7-, 8-, 9-, 10-, 11-, or
12-membered bicyclic heterocyclic ring system which comprises at
least one non-aromatic (i.e. saturated or partially unsaturated)
ring which consists of carbon atoms and from one to four,
preferably up to three, heteroatoms selected from the group
consisting of N, O and S, wherein the nitrogen and sulfur atoms may
optionally be oxidized as N-oxide, sulfoxide or sulfone, and
wherein the nitrogen atom may optionally be quaternized. A
heterocycle can be bonded via a ring carbon atom or, if available,
via a ring nitrogen atom. Bicyclic heterocyclic ring systems may be
fused, bridged, or spiro bicyclic heterocyclic ring system(s). In
some embodiments, heterocyclyl is monocyclic having 4 to 7,
preferably 4 to 6, ring atoms, of which 1 or 2 are heteroatoms
independently selected from the group consisting of N, O and S. In
some embodiments, a heterocyclyl group is bicyclic, and in which
case, the second ring may be an aromatic or a non-aromatic ring
which consists of carbon atoms and from one to four, preferably up
to three, heteroatoms independently selected from the group
consisting of N, O and S, or the second ring may be a benzene ring,
or a "cycloalkyl", or a "cycloalkenyl", as defined herein. Examples
of such heterocyclic groups include, but are not limited to
azetidine, chroman, dihydrofuran, dihydropyran, dioxane, dioxolane,
hexahydroazepine, imidazolidine, imidazoline, indoline, isochroman,
isoindoline, isothiazoline, isothiazolidine, isoxazoline,
isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane,
piperazine, piperidine, dihydropyridine, tetrahydropyridine,
dihydropyridazine, pyran, pyrazolidine, pyrazoline, pyrrolidine,
pyrroline, tetrahydrofuran, tetrahydropyran, thiamorpholine,
tetrahydrothiophene, thiazoline, thiazolidine, thiomorpholine,
thietane, thiolane, sulfolane, 1,3-dioxolane, 1,3-oxazolidine,
1,3-thiazolidine, tetrahydrothiopyran, tetrahydrotriazine,
1,3-dioxane, 1,4-dioxane, hexahydrotriazine, tetrahydro-oxazine,
tetrahydropyrimidine, perhydroazepine, perhydro-1,4-diazepine,
perhydro-1,4-oxazepine, 7-azabicyclo[2.2.1]heptane,
3-azabicyclo[3.2.0]heptane, 7-azabicyclo[4.1.0]heptane,
2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane,
tropane, 2-oxa-6-azaspiro[3.3]heptane, dihydrobenzofuran,
dihydrobenzimidazolyl, dihydrobenzoxazole, and
dihydrobenzothiazolyl, and N-oxides or sulfones or sulfoxides
thereof.
[0611] The term "cycloalkyl" refers to a fully saturated
monocyclic, bicyclic, tricyclic or other polycyclic hydrocarbon
group having the indicated number of ring carbon atoms. Multicyclic
cycloalkyl may be fused, bridged or spiro ring systems. Cycloalkyl
groups include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl
(bicyclo[2.2.1]heptyl), decalinyl, adamantyl, spiropentyl,
bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, spiro[2.4]heptyl,
spiro[2.5]octyl, bicyclo[5.1.0]octyl, spiro[2.6]nonyl,
bicyclo[2.2.0]hexyl, spiro[3.3]heptyl, bicyclo[4.2.0]octyl,
bicyclo[2.2.2]octyl, and spiro[3.5]nonyl. In some embodiments,
cycloalkyl is a monocyclic C.sub.3-8cycloalkyl. In other
embodiments, cycloalkyl is a bi- or tricyclic C.sub.5-12cycloalkyl.
In other embodiments, cycloalkyl is a spirocyclic
C.sub.5-12cycloalkyl.
[0612] The term "cycloalkenyl" refers to partially unsaturated
monocyclic, bicyclic, tricyclic, or other polycyclic hydrocarbon
groups. A ring carbon (e.g., saturated or unsaturated) is the point
of attachment of the cycloalkenyl substituent. Cycloalkenyl
moieties can include, e.g., cyclopentenyl, cyclohexenyl,
cyclohexadienyl, or norbornenyl. In some embodiments, a
cycloalkenyl is a C.sub.4-10cycloalkenyl. In other embodiments, a
cycloalkenyl is a C.sub.4-6cycloalkenyl. In some embodiments, a
cycloalkenyl is monocyclic. In some embodiments, a cycloalkenyl is
bicyclic.
[0613] The term "aryl" as used herein, is intended to mean any
stable monocyclic or bicyclic carbon ring of up to 6 members in
each ring, wherein at least one ring is aromatic. Examples of aryl
include phenyl, naphthyl, tetrahydronaphthyl, indanyl, or
biphenyl.
[0614] The term "heteroaryl", as used herein except where noted,
represents a stable 5-, 6- or 7-membered monocyclic- or stable 9 or
10-membered fused bicyclic ring system which comprises at least one
aromatic ring, which consists of carbon atoms and from one to four,
preferably up to three, heteroatoms selected from the group
consisting of N, O and S wherein the nitrogen and sulfur
heteroatoms may optionally be oxidized, and the nitrogen heteroatom
may optionally be quaternized. In the case of a "heteroaryl" which
is a bicyclic group, the second ring need not be aromatic and need
not comprise a heteroatom. Accordingly, bicyclic "heteroaryl"
includes, for example, a stable 5- or 6-membered monocyclic
aromatic ring consisting of carbon atoms and from one to four,
preferably up to three, heteroatoms, as defined immediately above,
fused to a benzene ring, or a second monocyclic "heteroaryl", or a
"heterocyclyl", a "cycloalkyl", or a "cycloalkenyl", as defined
above. Examples of heteroaryl groups include, but are not limited
to, benzimidazole, benzopyrazole, benzisothiazole, benzisoxazole,
benzofuran, isobenzofuran, benzothiazole, benzothiophene,
benzotriazole, benzoxazole, cinnoline, furan, furazan, imidazole,
indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole,
naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine,
pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,
quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole,
thiazole, thiophene, triazine, triazole, benzimidazole,
benzothiadiazole, isoindole, pyrrolopyridines, imidazopyridines
such as imidazo[1,2-a]pyridine, pyrazolopyridine, pyrrolopyrimidine
and N-oxides thereof.
[0615] The term "acyl", as used herein, refers to those groups
derived from an organic acid by removal of the hydroxy portion of
the acid. Accordingly, acyl is meant to include, for example,
acetyl, propionyl, butyryl, decanoyl, pivaloyl, benzoyl and the
like.
[0616] As used herein, the term "fused" refers to a connectivity
between two rings in which two adjacent atoms sharing at least one
bond (saturated or unsaturated) are common to the rings. For
example, in the following structure, rings A and B are fused
##STR00016##
Examples of fused ring structures include, but are not limited to,
decahydronaphthalene, 1H-indole, quinolone, chromane,
bicyclo[2.1.0]pentane and
6,7,8,9-tetrahydro-5H-benzo[7]annulene.
[0617] As used herein, the term "bridged" refers to a connectivity
wherein three or more atoms are shared between two rings. The
following structures
##STR00017##
are examples of "bridged" rings because the indicated atoms are
shared between at least two rings. Examples of bridged ring
structures include, but are not limited to, bicyclo[1.1.1]pentane,
2-oxabicyclo[1.1.1]pentane, 5-azabicyclo[2.1.1]hexane,
6-azabicyclo[3.1.1]heptane, adamantane and norbornane.
[0618] As used herein, the term "spiro" refers to a connectivity
between two rings wherein the rings have only one atom in common.
For example, in the structure
##STR00018##
rings C and D are joined by a spiro connection. Examples of spiro
connected ring structures include, but are not limited to,
spiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane,
2-oxa-6-azaspiro[3.3]heptane, spiro[4.5]decane and
2,6-dioxaspiro[3.3]heptane.
[0619] For each of the organic radicals defined above, any atom can
be optionally substituted, e.g., by one or more substituents.
[0620] Unless otherwise specified, when a bond is depicted in a
chemical structure with , it is meant that the bond is located at a
stereocenter in which the structure may have either the S or R
configuration as understood under the Cahn-Ingold System for naming
enantiomers. For example, the notation can indicate that the bond
at the given position can be either a or a . The presence of the
does not limit the exemplified compound to only a racemate, but can
include all possible stereoconfigurations.
[0621] It is understood that in structural formulae containing the
Y variable in which Y may be --NHC(O)--, the group is meant to be
unidirectional, i.e. the carbonyl is linked to the nitrogen to form
a urea group.
[0622] The term "treating", "treat", or "treatment" refers
generally to controlling, alleviating, ameliorating, slowing the
progress of or eliminating a named condition once the condition has
been established. In addition to its customary meaning, the term
"preventing", "prevent", or "prevention" also refers to delaying
the onset of, or reducing the risk of developing a named condition
or of a process that can lead to the condition, or the recurrence
of symptoms of a condition.
[0623] The term "therapeutically effective amount" or "effective
amount" is an amount sufficient to effect beneficial or desired
clinical results. An effective amount can be administered in one or
more administrations. An effective amount is typically sufficient
to palliate, ameliorate, stabilize, reverse, slow or delay the
progression of the disease state.
Compound Forms and Salts
[0624] The compounds of this disclosure may contain one or more
asymmetric centers and thus occur as racemates and racemic
mixtures, enantiomerically enriched mixtures, single enantiomers,
individual diastereomers and diastereomeric mixtures. The compounds
of the present disclosure may, either by nature of asymmetric
centers or by restricted rotation, be present in the form of
isomers (e.g., enantiomers, diastereomers).
[0625] It will also be appreciated that when two or more asymmetric
centers are present in the compounds of the disclosure, several
diastereomers and enantiomers of the exemplified structures will
often be possible, and that pure diastereomers and pure enantiomers
represent preferred embodiments. It is intended that pure
stereoisomers, pure diastereomers, pure enantiomers, and mixtures
thereof, are within the scope of the disclosure.
[0626] All isomers, whether separated, pure, partially pure, or in
racemic mixture, of the compounds of this disclosure are
encompassed within the scope of this disclosure. The purification
of said isomers and the separation of said isomeric mixtures may be
accomplished by standard techniques known in the art. For example,
diastereomeric mixtures can be separated into the individual
isomers by chromatographic processes or crystallization, and
racemates can be separated into the respective enantiomers either
by chromatographic processes on chiral phases or by resolution.
[0627] The compounds of the present disclosure include all cis,
trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as
mixtures thereof. The compounds of the present disclosure may also
be represented in multiple tautomeric forms, in such instances, the
present disclosure expressly includes all tautomeric forms of the
compounds described herein, even though only a single tautomeric
form may be represented. In addition, where a term used in the
present disclosure encompasses a group that may tautomerize, all
tautomeric forms are expressly included thereunder. For example,
hydroxy substituted heteroaryl includes 2-hydroxypyridine as well
as 2-pyridone, 1-hydroxyisoquinoline as well as
1-oxo-1,2-dihydroisoquinoline, and the like. All such isomeric
forms of such compounds are expressly included in the present
disclosure.
[0628] The compounds of the present disclosure include the
compounds themselves, as well as their salts, solvate, solvate of
the salt and their prodrugs, if applicable. Salts for the purposes
of the present disclosure are preferably pharmaceutically
acceptable salts of the compounds according to the present
disclosure. Salts which are not themselves suitable for
pharmaceutical uses but can be used, for example, for isolation or
purification of the compounds according to the disclosure are also
included. A salt, for example, can be formed between an anion and a
positively charged substituent (e.g., amino) on a compound
described herein. Suitable anions include chloride, bromide,
iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate,
trifluoroacetate, and acetate. Likewise, a salt can also be formed
between a cation and a negatively charged substituent (e.g.,
carboxylate) on a compound described herein. Suitable cations
include sodium ion, potassium ion, magnesium ion, calcium ion, and
an ammonium cation such as tetramethylammonium ion.
[0629] As used herein, "pharmaceutically acceptable salts" refer to
derivatives wherein the parent compound is modified by making acid
or base salts thereof. Examples of pharmaceutically acceptable
salts include, but are not limited to, mineral or organic acid
salts of basic residues such as amines; alkali or organic salts of
acidic residues such as carboxylic acids; and the like. When the
compound of the present disclosure is basic, pharmaceutically
acceptable salts include the conventional non-toxic salts or the
quaternary ammonium salts of the parent compound formed, for
example, from non-toxic inorganic or organic acids. For example,
such conventional non-toxic salts include those derived from
inorganic acids such as hydrochloric, hydrobromic, sulfonic,
sulfuric, sulfamic, phosphoric, nitric and the like; and the salts
prepared from organic acids such as acetic, propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, benzenesulfonic,
toluenesulfonic, naphthalenedisulfonic, methanesulfonic,
ethanesulfonic, ethanedisulfonic, camphorsulfonic, gluconic,
mandelic, mucic, pantothenic, oxalic, isethionic, and the like.
[0630] When the compound of the present disclosure is acidic, salts
may be prepared from pharmaceutically acceptable non-toxic bases,
including inorganic and organic bases. Such salts that may be
prepared include lithium salt, sodium salt, potassium salt,
magnesium salt, calcium salt, dicyclohexylamine salt,
N-methyl-D-glucamine salt, tris(hydroxymethyl)methylamine salt,
arginine salt, lysine salt, and the like.
[0631] Lists of suitable salts may be found in Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton,
Pa., 1985, p. 1418; S. M. Berge et al., "Pharmaceutical Salts", J.
Pharm. Sci. 1977, 66, 1-19; and "Pharmaceutical Salts: Properties,
Selection, and Use. A Handbook"; Wermuth, C. G. and Stahl, P. H.
(eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN
3-906390-26-8]; each of which is incorporated herein by reference
in its entirety.
[0632] Solvates in the context of the present disclosure are
designated as those forms of the compounds according to the present
disclosure which form a complex in the solid or liquid state by
stoichiometric coordination with solvent molecules. Hydrates are a
specific form of solvates, in which the coordination takes place
with water. Hydrates are preferred solvates in the context of the
present disclosure. The formation of solvates is described in
greater detail in "Solvents and Solvent Effects in Organic
Chemistry"; Reichardt, C. and Welton T.; John Wiley & Sons,
2011 [ISBN: 978-3-527-32473-6], the contents of which is
incorporated herein by reference in its entirety. A person of
ordinary skill in the art would recognize the solvates of the
present disclosure.
[0633] The present disclosure also encompasses all suitable
isotopic variants of the compounds according to the present
disclosure, whether radioactive or not. An isotopic variant of a
compound according to the present disclosure is understood to mean
a compound in which at least one atom within the compound according
to the present disclosure has been exchanged for another atom of
the same atomic number, but with a different atomic mass than the
atomic mass which usually or predominantly occurs in nature.
Examples of isotopes which can be incorporated into a compound
according to the present disclosure are those of hydrogen, carbon,
nitrogen, oxygen, fluorine, chlorine, bromine and iodine, such as
.sup.2H (deuterium), .sup.3H (tritium), .sup.13C, .sup.14C,
.sup.15N, .sup.17O, .sup.18O, .sup.18F, .sup.36Cl, .sup.82Br,
.sup.123I, .sup.124I, .sup.125I, .sup.129I and .sup.131I.
Particular isotopic variants of a compound according to the present
disclosure, especially those in which one or more radioactive
isotopes have been incorporated, may be beneficial, for example,
for the examination of the mechanism of action or of the active
compound distribution in the body. Due to comparatively easy
preparability and detectability, especially compounds labelled with
.sup.3H, .sup.14C and/or .sup.18F isotopes are suitable for this
purpose. In addition, the incorporation of isotopes, for example of
deuterium, can lead to particular therapeutic benefits as a
consequence of greater metabolic stability of the compound, for
example an extension of the half-life in the body or a reduction in
the active dose required. Such modifications of the compounds
according to the present disclosure may therefore in some cases
also constitute a preferred embodiment of the present disclosure.
In some embodiments, hydrogen atoms of the compounds described
herein may be replaced with deuterium atoms. Isotopic variants of
the compounds according to the present disclosure can be prepared
by processes known to those skilled in the art, for example by the
methods described below and the methods described in the working
examples, by using corresponding isotopic modifications of the
particular reagents and/or starting compounds therein.
[0634] The present disclosure includes within its scope prodrugs of
the compounds of Formula I. Prodrugs are generally drug precursors
that, following administration to a subject are converted to an
active, or a more active species via some process, such as
conversion by chemical hydrolysis or a metabolic pathway. Thus, in
the methods of treatment of the present disclosure, the terms
"administration of" or "administering a" compound shall encompass
the treatment of the various conditions described with the compound
specifically disclosed or with a compound which may not be
specifically disclosed, but which converts to the specified
compound in vivo after administration to the patient. Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described, for example, in "Design of Prodrugs,"
ed. H. Bundgaard, Elsevier, 1985 (Amsterdam, NL). Examples of
prodrugs include C.sub.1-6 alkyl esters of carboxylic acid groups
and esters of boronic acids, which, upon administration to a
subject, are capable of providing active compounds.
[0635] Esters of boronic acids are illustrated by Formula II:
##STR00019##
wherein:
[0636] Y.sub.1 and Y.sub.2 are each independently selected from
hydrogen, optionally substituted C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, C.sub.1-6heterocycle, aryl and heteroaryl, or
Y.sub.1 and Y.sub.2 are joined together to form the group
##STR00020##
which represents an optionally substituted C.sub.2-6alkyl in which
a carbon atom may be replaced by O, S or N--CH.sub.3, optionally
substituted C.sub.5-12cycloalkyl, optionally substituted
heterocycle, optionally substituted aryl or optionally substituted
heteroaryl. The optional substituents include, for example,
hydroxyl, halogen and C.sub.1-3alkoxy. As will be appreciated by
one of skill in the art, the squiggly lines describe the point at
which the moiety shown is attached to the parent molecule.
Illustrating the boronic acid esters are:
##STR00021##
[0637] Y.sub.1 and Y.sub.2 can also represent --B--O--B-- to form a
6-membered trioxatriborinane or --B-- to form a 4-membered
dioxadiboretane.
##STR00022##
[0638] In some embodiments, where W of Formula I is
--C(O)C(O)NR.sup.7R.sup.8 (ketoamides), compounds of Formula I may
be prepared as prodrugs. Examples of ketone prodrugs include but
are not limited to ketimine, oxime, aminal, ketal, hemiaminal,
hemiketal, thioketal, hydrated ketone which, upon administration to
a subject, are capable of providing active compounds. Carbonyl
derivatives of ketoamides are illustrated by Formula IIIa and
IIIb:
##STR00023##
wherein:
[0639] X.sub.1 and X.sub.2 are each independently selected from O,
N and S;
[0640] Y.sub.1 and Y.sub.2 are each independently selected from
hydrogen, optionally substituted C.sub.1-6alkyl,
C.sub.3-10cycloalkyl, C.sub.1-6heterocycle, or Y.sub.1 and Y.sub.2
are joined together to form the group:
##STR00024##
wherein Y.sub.1 and Y.sub.2 forms an optionally substituted
C.sub.2-6alkyl, or an optionally substituted heterocycle. The
optional substituents include, for example, hydroxyl, halogen and
C.sub.1-3alkoxy;
[0641] Y.sub.3 is H, C.sub.1-4alkyl, OH or O--C.sub.1-4alkyl.
[0642] Illustrating the ketone prodrugs are:
##STR00025##
Pharmaceutical Compositions
[0643] The term "pharmaceutical composition" as used herein is
intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) that make up the
carrier, as well as any product which results, directly or
indirectly, from combination, complexation or aggregation of any
two or more of the ingredients, or from dissociation of one or more
of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients. Accordingly, the
pharmaceutical compositions of the present disclosure encompass any
composition made by admixing a compound of the present disclosure,
or a pharmaceutically acceptable salt, or solvate or solvate of the
salt thereof, and a pharmaceutically acceptable carrier.
[0644] The term "pharmaceutically acceptable carrier" refers to a
carrier or an adjuvant that may be administered to a patient,
together with a compound of the present disclosure, or a
pharmaceutically acceptable salt, solvate, salt of the solvate or
prodrug thereof, and which does not destroy the pharmacological
activity thereof and is nontoxic when administered in doses
sufficient to deliver a therapeutic amount of the compound.
[0645] The amount administered depends on the compound formulation,
route of administration, etc. and is generally empirically
determined in routine trials, and variations will necessarily occur
depending on the target, the host, and the route of administration,
etc. Generally, the quantity of active compound in a unit dose of
preparation may be varied or adjusted from about 1, 3, 10 or 30 to
about 30, 100, 300 or 1000 mg, according to the particular
application. For convenience, the total daily dosage may be divided
and administered in portions during the day if desired.
[0646] Pharmaceutical compositions of the present disclosure for
injection comprise pharmaceutically acceptable sterile aqueous or
non-aqueous solutions, dispersions, suspensions or emulsions as
well as sterile powders for reconstitution into sterile injectable
solutions or dispersions just prior to use. Examples of suitable
aqueous and non-aqueous carriers, diluents, solvents or vehicles
include water, ethanol, polyols (such as glycerol, propylene
glycol, polyethylene glycol, and the like), and suitable mixtures
thereof, vegetable oils (such as olive oil), and injectable organic
esters such as ethyl oleate. Proper fluidity can be maintained, for
example, by the use of coating materials such as lecithin, by the
maintenance of the required particle size in the case of
dispersions, and by the use of surfactants.
[0647] These pharmaceutical compositions may also contain adjuvants
such as preservative, wetting agents, emulsifying agents, and
dispersing agents. Prevention of the action of micro-organisms may
be ensured by the inclusion of various antibacterial and antifungal
agents, for example, paraben, chlorobutanol, phenol sorbic acid,
and the like. It may also be desirable to include isotonic agents
such as sugars, sodium chloride, and the like. Prolonged absorption
of the injectable pharmaceutical form may be brought about by the
inclusion of agents that delay absorption such as aluminium
monostearate and gelatin. If desired, and for more effective
distribution, the compounds can be incorporated into slow release
or targeted delivery systems such as polymer matrices, liposomes,
and microspheres.
[0648] The pharmaceutical compositions that are injectable
formulations can be sterilised, for example, by filtration through
a bacterial-retaining filter, or by incorporating sterilising
agents in the form of sterile solid pharmaceutical compositions
that can be dissolved or dispersed in sterile water or other
sterile injectable medium just prior to use.
[0649] Solid dosage forms of the instant pharmaceutical
compositions for oral administration include capsules, tablets,
pills, powders, and granules. In such solid dosage forms, the
active compound is mixed with at least one inert, pharmaceutically
acceptable excipient or carrier such as sodium citrate or dicalcium
phosphate and/or a) fillers or extenders such as starches, lactose,
sucrose, glucose, mannitol, and silicic acid, b) binders such as,
for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as
glycerol, d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0650] Solid pharmaceutical compositions of a similar type may also
be employed as fillers in soft and hard-filled gelatin capsules
using such excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols and the like.
[0651] The solid dosage forms of the instant pharmaceutical
compositions of tablets, dragees, capsules, pills, and granules can
be prepared with coatings and shells such as enteric coatings and
other coatings well known in the pharmaceutical formulating art.
They may optionally contain opacifying agents and can also be of a
formulation that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding
pharmaceutical compositions which can be used include polymeric
substances and waxes.
[0652] The active compounds can also be in microencapsulated form,
if appropriate, with one or more of the above-mentioned
excipients.
[0653] Liquid dosage forms of the instant pharmaceutical
compositions for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups and elixirs.
In addition to the active compounds, the liquid dosage forms may
contain inert diluents commonly used in the art such as, for
example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl
carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene
glycols and fatty acid esters of sorbitan, and mixtures
thereof.
[0654] Besides inert diluents, the oral pharmaceutical compositions
can also include adjuvants such as wetting agents, emulsifying and
suspending agents, sweetening, flavouring, and perfuming
agents.
[0655] Suspensions of the instant compounds, in addition to the
active compounds, may contain suspending agents as, for example,
ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and
sorbitan esters, microcrystalline cellulose, aluminium
metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures
thereof.
[0656] Pharmaceutical compositions for rectal or vaginal
administration are preferably suppositories which can be prepared
by mixing the compounds with suitable non-irritating excipients or
carriers such as cocoa butter, polyethylene glycol or a suppository
wax which are solid at room temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and
release the active compound.
[0657] Dosage forms for topical administration of a compound or
pharmaceutical composition of the present disclosure include
powders, patches, sprays, ointments and inhalants. The active
compound is mixed under sterile conditions with a pharmaceutically
acceptable carrier and any needed preservatives, buffers, or
propellants which may be required.
[0658] Dosage forms for application to the eye include solutions,
suspensions, ointments, gels, emulsions, strips, inserts such as
contact lenses, and implants, which may be administered topically,
intravitreally, perioccularly, and the like.
Uses
[0659] The present disclosure is directed to novel heterocyclic
prolinamide derivatives of Formula I, and pharmaceutically
acceptable salts, solvates, salts of solvates and prodrugs thereof,
useful in the prevention (e.g., delaying the onset of or reducing
the risk of developing) and treatment (e.g., controlling,
alleviating, or slowing the progression of) of age-related macular
degeneration (AMD) and related diseases of the eye. These diseases
include dry-AMD, wet-AMD, geographic atrophy, diabetic retinopathy,
retinopathy of prematurity, polypoidal choroidal vasculopathy,
diabetic macula edema (DME), other retinopathies such as choroidal
neovascularisation (CNV), choroidal neovascular membrane (CNVM),
cystoid macular edema (CME), epi-retinal membrane (ERM) and macular
hole, hypertrophic changes of the retinal pigment epithelium (RPE),
atrophic changes of the retinal pigment epithelium, retinal
detachment, choroidal vein occlusion, retinal vein occlusion,
corneal angiogenesis following, for example, keratitis, cornea
transplantation or keratoplasty, corneal angiogenesis due to
hypoxia (e.g., induced by extensive contact lens wearing),
pterygium conjunctivae, subretinal edema, intraretinal edema,
Stargardt disease and degeneration of retinal or photoreceptor
cells. The present disclosure disclosed herein is further directed
to methods of prevention, slowing the progress of, and treatment of
dry-AMD, wet-AMD, and geographic atrophy, diabetic retinopathy,
retinopathy of prematurity, polypoidal choroidal vasculopathy,
diabetic macula edema (DME), other retinopathies such as choroidal
neovascularisation (CNV), choroidal neovascular membrane (CNVM),
cystoid macular edema (CME), epi-retinal membrane (ERM) and macular
hole, hypertrophic changes of the retinal pigment epithelium (RPE),
atrophic changes of the retinal pigment epithelium, retinal
detachment, choroidal vein occlusion, retinal vein occlusion,
corneal angiogenesis following, for example, keratitis, cornea
transplantation or keratoplasty, corneal angiogenesis due to
hypoxia (e.g., induced by extensive contact lens wearing),
pterygium conjunctivae, subretinal edema, intraretinal edema,
Stargardt disease and degeneration of retinal or photoreceptor
cells, comprising: administration of a therapeutically effective
amount of compound of the present disclosure. The compounds of the
present disclosure are inhibitors of HTRA1. Thus, the compounds of
the present disclosure are useful in the prevention and treatment
of a wide range diseases mediated (in whole or in part) by HTRA1.
The compounds of the present disclosure are also useful for
inhibiting HTRA1 protease activity in an eye and elsewhere. By
virtue of their activity profile, the compounds of the present
disclosure are particularly suitable for the treatment and/or
prevention of ocular disorders, such as age-related macular
degeneration (AMD) like wet-AMD or dry-AMD, geographic atrophy,
diabetic retinopathy, Stargardt disease, choroidal
neovascularisation (CNV), and diabetic macula edema (DME).
[0660] Additionally, compounds of the present disclosure may be
useful in the treatment of other diseases in which HTRA1 may be
involved, including retinal angiomatous proliferation, foveomacular
proliferation, musculoskeletal diseases, including osteoarthritis,
spinal disk degeneration rheumatoid arthritis, muscular dystrophy
and osteoporosis, and treatment of autologous chondrocytes prior to
intraarticular implantation.
Administration
[0661] The compounds and compositions described herein can, for
example, be administered orally, parenterally (e.g.,
subcutaneously, intracutaneously, intravenously, intramuscularly,
intraarticularly, intraarterially, intrasynovially, intrasternally,
intrathecally, intralesionally and by intracranial injection or
infusion techniques), by inhalation spray, topically, rectally,
nasally, buccally, vaginally, via an implanted reservoir, by
injection, subdermally, intraperitoneally, transmucosally, or in an
ophthalmic preparation, with a dosage ranging from about 0.01 mg/kg
to about 1000 mg/kg, (e.g., from about 0.01 to about 100 mg/kg,
from about 0.1 to about 100 mg/kg, from about 1 to about 100 mg/kg,
from about 1 to about 10 mg/kg) every 4 to 120 hours, or according
to the requirements of the particular drug, dosage form, and/or
route of administration. The interrelationship of dosages for
animals and humans (based on milligrams per meter squared of body
surface) is described by Freireich et al., Cancer Chemother. Rep.
50, 219-244 (1966). Body surface area may be approximately
determined from height and weight of the patient. See, e.g.,
Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 537
(1970). In certain embodiments, the compositions are administered
by oral administration or by injection. The methods herein
contemplate administration of an effective amount of compound or
compound composition to achieve the desired or stated effect.
Typically, the pharmaceutical compositions of the present
disclosure will be administered from about 1 to about 6 times per
day or alternatively, as a continuous infusion. Such administration
can be used as a chronic or acute therapy.
[0662] Lower or higher doses than those recited above may be
required. Specific dosage and treatment regimens for any particular
patient will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body weight,
general health status, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
disease, condition or symptoms, the patient's disposition to the
disease, and the judgment of the treating physician.
[0663] Dosage forms include from about 0.001 milligrams to about
2,000 milligrams (including, from about 0.001 milligrams to about
1,000 milligrams, from about 0.001 milligrams to about 500
milligrams, from about 0.01 milligrams to about 250 milligrams,
from about 0.01 milligrams to about 100 milligrams, from about 0.05
milligrams to about 50 milligrams, and from about 0.1 milligrams to
about 25 milligrams) of a compound of Formula I (and/or a compound
of any of the other formulae described herein) or a salt (e.g., a
pharmaceutically acceptable salt) thereof as defined anywhere
herein. The dosage forms can further include a pharmaceutically
acceptable carrier and/or an additional therapeutic agent.
[0664] With regard to ophthalmic preparation, because AMD and
related diseases (including dry-AMD, Wet-AMD, geographic atrophy,
diabetic retinopathy, retinopathy of prematurity, polypoidal
choroidal vasculopathy, and degeneration of retinal or
photoreceptor cells) primarily afflict the back of the eye, local
administration such as topical administration, trans-scleral drug
delivery and intravitreal administration may be preferable over
systemic administration. Intravitreal administration can be further
divided into intravitreal injection and intravitreal implants. Of
these, intravitreal injection appears to be the most widely used.
Products utilizing intravitreal injection include Trivaris.RTM.
(triamcinolone acetonide), Triescence.RTM. (triamcinolone
acetonide, Alcon Fort Worth, Tex.), Macugen.RTM. (pegaptanib
sodium, Bausch and Lomb, Rochester, N.Y.), Lucentis.RTM.
(ranibizumab injection, Genentech, South San Francisco, Calif.),
Ozurdex.RTM. (dexamethasone, Allergan, Inc., Irvine, Calif.) and
Iluvien.RTM. (flucinolone acetonide, Alimera Sciences, Alpharetta,
Ga.). The preferred dosage range for local administration to the
back of the eye ranges from 0.001 mg to 100 mg (including from
about 0.01 milligrams to about 500 milligrams, from about 0.05
milligrams to about 250 milligrams, from about 0.05 milligrams to
about 100 milligrams, from about 0.1 milligrams to about 50
milligrams, from about 0.1 milligrams to about 25 milligrams, and
from about 0.1 milligrams to about 10 milligrams). References on
the subject of ophthalmic drug delivery include: [0665] Kompella U.
B. et al., Recent Advances in Ophthalmic Drug Delivery, Ther.
Deliv. 2010 1(3): 435-456; [0666] Gaudana R. et al., Ocular Drug
Delivery, AAPS Journal, Vol. 12, No. 3: 348-360 (2010); [0667]
Haghjou N. et al., Sustained Release Intraocular Drug Delivery
Devices for Treatment of Uveitis, J. Ophthalmic Vis. Res. 2011; 6
(4): 317-329; [0668] Kuno N. and Fujii S. Recent Advances in Ocular
Drug Delivery Systems, Polymers (2011), 3:193-221; [0669] Patel A.
et al., Ocular Drug Delivery Systems: An Overview, World J.
Pharmacol. (2013) 2:47-64; [0670] Morrison P. W. J. and
Khutoryanskiy V. V. Advances in Ophthalmic Drug Delivery, Ther.
Deliv. (2014) 5:1297-1315; [0671] Chen H. Recent Developments in
Ocular Drug Delivery, J. Drug Target (2015), 23:597-604; all of
which are incorporated by reference.
[0672] For the treatment and/or prevention of ocular disorders, as
described above, the preferred route for administering the
compounds of the present disclosure is topically at the eye or by
an ocular drug delivery system. Intraocular injections are another
way to administer the compounds of the present disclosure that is
suitable for such purposes.
[0673] Delivery to areas within the eye can be accomplished by
injection, employing a cannula or another invasive device designed
to introduce precisely metered amounts of a desired formulation to
a particular compartment or tissue within the eye (e.g., posterior
chamber or retina). An intraocular injection may be into the
vitreous (intravitreal), under the conjunctiva (subconjunctival),
behind the eye (retrobulbar), into the sclera, or under the Capsule
of Tenon (sub-Tenon), and may be in a depot form. Other intraocular
routes of administration and injection sites and forms are also
contemplated and are within the scope of the present
disclosure.
[0674] The compounds according to the present disclosure may be
formulated in a manner known to those skilled in the art so as to
give adequate delivery to the back of the eye, which may be by
regular dosing, such as with eye drops, or by using a delivery
system to give a controlled release, such as slow release, of the
compounds according to the present disclosure.
[0675] Preferred ocular formulations for the compounds of the
present disclosure include aqueous solutions, suspensions or gels
of these compounds in the form of drops of liquid, liquid washes,
sprays, ointments or gels, in a mixture with excipients suitable
for the manufacture and use of such application forms.
Alternatively, the compounds of the present disclosure may be
applied to the eye via liposomes or other ocular delivery systems
that are known in the art.
[0676] Appropriate dosage levels may be determined by any suitable
method known to one skilled in the art of treating eye diseases.
Preferably, the active substance is administered at a frequency of
1 to 4 times per day for topical administration, or less often if a
drug delivery system is used. Typically, an ocular formulation
intended for topical application contains the active ingredient in
a concentration range of about 0.0010% to 10%.
[0677] Nevertheless, actual dosage levels and time course of
administration of the active ingredients in the pharmaceutical
compositions of the present disclosure may be varied so as to
obtain an amount of the active ingredient which is effective to
achieve the desired therapeutic response for a particular patient,
composition and mode of administration, without being toxic to the
patient. It may therefore be necessary where appropriate to deviate
from the stated amounts, in particular as a function of age,
gender, body weight, diet and general health status of the patient,
route of administration, individual response to the active
ingredient, nature of the preparation, and time or interval over
which administration takes place. Thus, it may be satisfactory in
some cases to manage with less than the aforementioned minimum
amount, whereas in other cases the stated upper limit must be
exceeded. It may in the event of administration of larger amounts
be advisable to divide these into multiple individual doses spread
over the day.
[0678] In one aspect the compounds of the present disclosure may be
co-administered with one or more additional agents. The additional
agents include, but are not limited to Acuvail.RTM. (ketorolac
tromethamine ophthalmic solution), AK-Con-A.RTM./OcuHist.RTM.
(pheniramine maleate-naphazoline HCl, ophthalmic solution),
Akten.RTM. (lidocaine HCl ophthalmic gel), Alamast.RTM. (pemirolast
potassium ophthalmic solution), Alphagan.RTM. (brimonidine tartrate
ophthalmic solution), Bepreve.RTM. (bepotastine besilate ophthalmic
solution), Besivance.RTM. (besifloxacin ophthalmic suspension),
Betaxon.RTM. (levobetaxolol HCl ophthalmic suspension), Cosopt.RTM.
(dorzolamide HCl--timolol maleate, ophthalmic solution),
Cystaran.RTM. (cysteamine HCl ophthalmic solution), Durezol.RTM.
(difluprednate ophthalmic emulsion), Eylea.RTM. (aflibercept
intravitreal injection), Jetrea.RTM. (ocriplasmin intravitreal
injection), Lotemax.RTM. (loteprednol etabonate ophthalmic
suspension), Lucentis.RTM. (ranibizumab injection), Lumigan.RTM.
(bimatoprost ophthalmic solution), Macugen.RTM. (pegaptanib
intravitreal injection), Ocuflox.RTM. (ofloxacin ophthalmic
solution), Omidria.RTM. (phenylephrine and ketorolac injection),
Ozurdex.RTM. (dexamethasone intravitreal implant), Quixin.RTM.
(levofloxacin ophthalmic solution), Rescula.RTM. (unoprostone
isopropyl ophthalmic solution 0.15%), Restasis.RTM. (cyclosporine
ophthalmic emulsion), Salagen.RTM. (pilocarpine HCl tablets),
Travatan.RTM. (travoprost ophthalmic solution), Valcyte.RTM.
(valganciclovir HCl tablets and oral solution), Vistide.RTM.
(cidofovir tablets), Visudyne.RTM. (verteporfin injection),
Vitrasert.RTM. (ganciclovir implant), Vitravene.RTM. (fomivirsen
injection), Zioptan.RTM. (tafluprost ophthalmic solution),
Zirgan.RTM. (ganciclovir ophthalmic gel), and Zymaxid.RTM.
(gatifloxacin ophthalmic solution). Furthermore the compounds of
the disclosure may be co-administered with one or more inhibitors
of VEGF-mediated angiogenesis, such as, for example, ACTB-1003
(Edding Pharm, CN), apatinib, axitinib, bevacizumab, bevasiranib,
BMS-690514 (Bristol-Myers Squibb (BMS), NY), brivanib, cediranib,
CT-322 (Adnexus/BMS, MA), dovitinib, lenvatinib, foretinib,
KH-902/conbercept (approved in CN for exudative macular
degeneration), linifanib, MGCD-265 (Mirati Therapeutics, CA),
motesanib, elpamotide, pazopanib, pegaptanib, ranibizumab,
regorafenib, ruboxystaurin, sorafenib, SU-14813 (Pfizer, CT),
sunitinib, telatinib, TG-100801, tivozanib, TSU-68 (Taiho
Pharmaceuticals, JP), vandetanib, vargatef, vatalanib and
Carbometyx.RTM. (cabozantinib tablets, Exelixis, CA), or with
inhibitors of other signaling pathways, such as disulfiram,
fenretinide, mecamylamine, PF-04523655 (Pfizer, CT), sonepcizumab,
tandospirone and volociximab.
[0679] Additional agents which may be utilized for
co-administration include: known vitamins and antioxidants such as
AREDS/AREDS2 (supplements used in Age-Related Eye Disease
Study/Study 2, National Eye Institute, US), omega-3 fatty acids,
lutein, zeaxanthin, vitamin A; visual-cycle modulators such as
emixustat (ACU-4429, Acucela, WA); anti-inflammatory agents such as
Illuvien.RTM. (fluocinolone acetonide), sirolimus,
Triesence.RTM./Trivaris.RTM. (triamcinolone acetonide); complement
modulators such as lampalizumab, Soliris.RTM. (eculizumab, Alexion,
CT); amyloid-modulators such as GSK933776 (GlaxosmithKline, PA),
RN6G (PF-04382923, Pfizer, CT) and platelet-derived growth factor
modulators such as, for example, Fovista.RTM. (pegpleranib,
Ophthotech, NY).
[0680] In certain embodiments, the additional agents may be
administered separately (e.g., sequentially; on different
overlapping schedules), as part of a multiple dose regimen, from
the compounds of the present disclosure (e.g., one or more
compounds of Formula (I) and/or a compound of any of the other
formulae, including any subgenera or specific compounds thereof).
In other embodiments, these agents may be part of a single dosage
form, mixed together with the compounds of the present disclosure
in a single composition. In still another embodiment, these agents
can be given as a separate dose that is administered at about the
same time as that of one or more compounds of Formula (I) (and/or a
compound of any of the other formulae, including any subgenera or
specific compounds thereof) are administered (e.g., simultaneously
with the administration of one or more compounds of Formula (I)
(and/or a compound of any of the other formulae, including any
subgenera or specific compounds thereof)). When the compositions of
the present disclosure include a combination of a compound of the
formulae described herein and one or more additional therapeutic or
prophylactic agents, both the compound and the additional agent can
be present at dosage levels of between about 1 to 100%, and more
preferably between about 5 to 95% of the dosage normally
administered in a monotherapy regimen.
[0681] The compositions of the present disclosure may contain any
conventional non-toxic pharmaceutically-acceptable carriers,
adjuvants or vehicles. In some cases, the pH of the formulation may
be adjusted with pharmaceutically acceptable acids, bases or
buffers to enhance the stability of the formulated compound or its
delivery form.
[0682] The compositions of the present disclosure may be orally
administered in any orally acceptable dosage form including, but
not limited to, capsules, tablets, emulsions and aqueous
suspensions, dispersions and solutions. In the case of tablets for
oral use, carriers which are commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried corn starch. When aqueous
suspensions and/or emulsions are administered orally, the active
ingredient may be suspended or dissolved in an oily phase and then
combined with emulsifying and/or suspending agents. If desired,
certain sweetening and/or flavoring and/or coloring agents may be
added.
Biological Function
[0683] The utility of the present disclosure can be demonstrated by
one or more of the following methods or other methods known in the
art:
Full Length HTRA1 Assay
[0684] Serial dilutions (1/3) from 1000 .mu.M down to 0.051 .mu.M
of test compounds were prepared in dimethyl sulfoxide (DMSO). Then
2 .mu.L of solution from each dilution were added to 100 .mu.L of 4
nM full-length human His-HTRA1 in assay buffer (50 mM Tris, pH 7.5,
200 mM NaCl and 0.25%
3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate or CHAPS)
in white non-binding 96-well plates. The assay solutions were mixed
for 5 seconds on a shaker plate and incubated for 10 minutes at
room temperature. Mca-H.sub.2OPT
(Mca-Ile-Arg-Arg-Val-Ser-Tyr-Ser-Phe-Lys(Dnp)-Lys-OH
trifluoroacetate salt) (Mca=7-methoxycoumarin-4-acetic acid;
Dnp=dinitrophenyl) (5 .mu.M) in 100 .mu.L of assay buffer was added
to the assay solutions. The reaction mixture was shaken for 5
seconds on a shaker plate and cleavage of Mca-H.sub.2OPT was
monitored by spectrofluorometry (SpectraMax M3 by Molecular
Devices, CA) for 10 minutes (Ex.lamda.=330 nm; Em.lamda.=420 nm).
Percent inhibition was calculated by fitting values to a standard
mathematical model for determining the dose response curve.
TABLE-US-00001 Example HTRA1 IC.sub.50 (.mu.M) 1 0.34 2 0.014 3
0.070 4 0.016 5 0.095 6 0.10 7 0.051 8 0.076 9 0.066 10 0.044 11
0.062 12 0.014 13 0.038 14 0.006 15 0.005 16 0.017 17 0.086 18
0.033 19 0.036 20 0.23 21 0.50 22 0.10 23 0.063 24 0.010 25 0.014
26 0.074 27 0.25 28 0.042 29 0.025 30 0.014 31 0.029 32 0.13 33
0.045 34 0.10 35 0.081 36 0.019 37 0.037 38 0.051 39 0.008 40 0.039
41 0.042 42 0.025 43 0.038 44 0.023 45 0.016 46 0.12 47 0.18 48
0.031 49 0.017 50 0.023 51 0.018 52 0.018 53 0.045 54 0.020 55
0.025 56 0.017 57 0.32 58 0.050 59 0.081 60 0.17 61 0.075 62 0.47
63 0.095 64 0.22 65 0.29 66 0.21 67 0.51 68 0.091 69 0.25 70 0.12
71 0.23 72 0.013 73 0.010 74 0.009 75 0.004 76 0.005 77 0.009 78
0.056 79 0.007 80 0.011 81 0.007 82 0.007 83 0.005 84 0.019 85
0.016 86 0.019 87 0.009 88 0.004 89 0.008 90 0.012 91 0.009 92
0.005 93 0.004 94 0.009 95 0.005 96 0.006 97 0.006 98 0.005 99
0.005 100 0.006 101 0.006 102 0.006 103 0.004 104 0.009 105 0.009
106 0.006 107 0.004 108 0.007 109 0.008 110 0.004 111 0.003 112
0.004 113 0.004 114 0.004 115 0.008 116 0.004 117 0.009 118 0.005
119 0.015 120 0.010 121 0.007 122 0.012 123 0.020 124 0.009 125
0.017 126 0.014 127 0.008 128 0.017 129 0.009 130 0.038 131 0.010
132 0.008 133 0.008 134 0.009 135 0.008 136 0.005 137 0.012 138
0.006 139 0.009 140 0.006 141 0.009 142 0.009 143 0.011 144 0.008
145 0.033 146 0.014 147 0.020 148 0.057 149 0.028 150 0.78 151
0.028 152 0.086 153 0.030 154 0.030 155 0.020 156 0.03 157 0.023
158 0.13 159 0.055 160 0.071 161 0.039 162 0.11 163 0.068 164 0.032
165 0.207
Synthesis
[0685] The starting materials used for the synthesis are either
synthesized or obtained from commercial sources, such as, but not
limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar,
Enamine, PharmaBlock, VWR Scientific, and the like. The reversed
phase and normal phase chromatography columns were purchased from
Teledyne ISCO, Inc. (NE), and the Isolute phase separators were
purchased from Biotage (NC). Nuclear Magnetic Resonance (NMR)
analysis was conducted using a Varian Mercury 300 MHz spectrometer
with an appropriate deuterated solvent. LCMS analysis was conducted
using a Waters Acquity UPLC with a QDA MS detector using a Waters
C18 BEH 1.7 .mu.M, 2.1.times.50 mm column, eluting with 95:5 to
0:100 H.sub.2O:MeCN+0.1% formic acid at a flow rate of 0.6 mL/min
over 3.5 minutes. The QDA MS detector was set up to scan under both
positive and negative mode ions ranging from 100-1200 Daltons.
General methods for the preparation of compounds can be modified by
the use of appropriate reagents and conditions for the introduction
of the various moieties found in the structures as provided
herein.
Abbreviations
[0686] ACN acetonitrile [0687] aq. aqueous [0688] Bn benzyl [0689]
BnNH.sub.2 benzylamine [0690] Boc tert-butyloxycarbonyl [0691]
Boc.sub.2O di-tert-butyl dicarbonate [0692] C Celsius [0693] conc.
concentrated [0694] Cp*RuCl(Ph.sub.3P).sub.2
chloro(pentamethylcyclopentadienyl)bis(triphenylphosphine)ruthenium
(II) [0695] d days [0696] DCM dichloromethane or methylene chloride
[0697] DEAD diethyl azodicarboxylate [0698] DIAD diisopropyl
azodicarboxylate [0699] DMA dimethylacetamide [0700] DMF
dimethylformamide [0701] DMP Dess-Martin periodinane [0702] DMSO
dimethylsulfoxide [0703] EDC
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0704]
Et ethyl [0705] EtOAc ethyl acetate [0706] Et.sub.2O diethylether
[0707] g gram [0708] h hour [0709] HATU
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate [0710] HOAt 1-hydroxy-7-azobenzotriazole
[0711] IBX 2-iodoxybenzoic acid [0712] L liter [0713] LAH lithium
aluminum hydride [0714] LC-MS liquid chromatography mass
spectrometry [0715] M molar [0716] mCPBA meta-chloroperoxybenzoic
acid [0717] MeOH methanol [0718] min minutes [0719] mg milligram
[0720] mmol millimoles [0721] Ms methanesulfonyl [0722] MsCl
methanesulfonyl chloride [0723] MTBE methyl t-butylether [0724] N
normality [0725] PCy.sub.3 HBF.sub.4 tricyclohexylphosphine
tetrafluoroborate [0726] Pd/C palladium on carbon [0727] iPr
isopropyl [0728] iPr.sub.2EtN or iPr.sub.2NEt diisopropylethylamine
or Hunig's base [0729] iPrOH isopropanol [0730] PyAOP
(7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluorophosphate [0731] sat. saturated [0732] TEA or Et.sub.3N
triethylamine [0733] THF tetrahydrofuran [0734] TLC thin layer
chromatography [0735] .mu.l microliter [0736] wt weight [0737]
X-Phos G2
chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-
-amino-1,1'-biphenyl)]palladium(II)
General Synthetic Scheme
[0738] In some embodiments, compounds described herein can be
prepared as outlined in the following general synthetic schemes.
These compounds may be viewed as consisting of four units as shown
in the general structure: A--the R.sup.1--Y group, B--an
.alpha.-amino acyl group, C--the prolyl group, and D--an
aminoheterocyclic group; and this shorthand notation is used below
to refer to such units and the various combinations thereof. All
the variables in the general structure and in the synthetic schemes
are, unless otherwise specified, as defined in the claims; the
triazole substituent R is a substituent for the heteroaryl group,
as defined in the claims.
General Structure
##STR00026##
[0739] Method I: Synthesis of Aminoheterocyclic 2-hydroxyacetamides
(I-6, D)
[0740] The reduction of a suitably protected (e.g., Boc-protected)
aminoheterocyclic carboxylic acid (I-1) to the corresponding
alcohol (I-2) using a reducing agent such as LAH, followed by
oxidation with, for example, DMP provides the aminoheterocyclic
aldehyde (I-3). Alternatively, the protected aminoheterocyclic
carboxylic acid (I-1) is coupled to N,O-dimethylhydroxylamine and
the resulting N-methoxy-N-methylacetamide (I-7) is reduced, using
for example LAH, to afford the corresponding aminoheterocyclic
aldehyde (I-3). The aldehyde is treated with KCN and NaHSO.sub.3 to
give the desired cyanohydrin (I-4), which can then be hydrolyzed to
the protected hydroxyacetamide (I-5) using standard basic
conditions such as K.sub.2CO.sub.3/H.sub.2O.sub.2 or urea hydrogen
peroxide/K.sub.2CO.sub.3 (similar to method as in Li, Yun-Long, et
al., PCT Int. Appl. 2015191677, Dec. 17, 2015). The
hydroxyacetamide (I-5) is then deprotected (e.g. using HCl for Boc)
to provide the aminoheterocyclic 2-hydroxyacetamide (I-6, D).
Alternatively, the cyanohydrins (I-4) can be hydrolyzed using conc.
HCl to provide the deprotected aminoheterocyclic 2-hydroxyacetamide
(I-6) in one step.
##STR00027##
[0741] The hydroxyl amides containing cyclic ethers, cyclic
sulfones or cyclic amides are oxidized to the corresponding
ketoamides using a number of oxidative reagents such as DMP or IBX.
The hydroxyamides containing a thio ether necessitate protection of
the sulfide (e.g. via the addition of stoichiometric Pd/C or
copper(II) acetate) to avoid oxidation of the thio ether to the
corresponding sulfoxide.
Method II: Synthesis of 4-triazoloproline Intermediates (II-5,
B-C)
[0742] The alcohol moiety of a protected 4-hydroxyproline ester
(II-1) is converted to a mesylate with MsCl and then reacted with
NaN.sub.3 to afford 4-azidoproline (II-2). The azide intermediate
is treated with substituted acetylenes in the presence of metal
catalysis to afford the triazole adduct (II-3; see Boren, B. C., et
a. J. Am. Chem. Soc. 2008, 130, 8923-8930 and Himo, F., et al. J.
Am. Chem. Soc. 2005, 127, 210-216). Deprotection of the proline
ring nitrogen, followed by coupling with another suitably protected
amino acid using standard amide coupling conditions provides the
triazoloproline (II-4). Hydrolysis of the ester under standard
basic conditions such as LiOH affords the triazoloproline
intermediate (II-5, B-C).
##STR00028##
Method III: Synthesis of 4-triazoloproline Intermediates (III-3,
A-B-C)
[0743] Alternatively, the azidoproline derivative (II-2) can be
directly deprotected with HCl and then coupled with a suitably
protected amino acid using standard amide coupling conditions to
form the azidoproline intermediate (III-1). Deprotection with HCl
followed by reaction with a carboxylic acid (or equivalent) using
standard amide coupling conditions provides the N-acyl azidoproline
intermediate (III-2). A [3+2] cycloaddition of this azide with a
substituted acetylene using a metal catalysis as in Boren, B. C.,
supra, or Himo, F. supra, followed by hydrolysis under standard
basic conditions such as LiOH gives the corresponding
triazoloproline intermediate (III-3, A-B-C).
##STR00029##
Method IV: Synthesis of Heterocyclic Ketoamides Intermediates
(IV-3, B-C-D)
[0744] The protected B-C triazoloproline acid (II-5) is coupled
with aminoheterocyclic 2-hydroxypropanamide (I-6, D) using standard
amide coupling procedures to provide the protected hydroxyamide
intermediate (IV-1). Oxidation of the hydroxyamide (IV-1) provides
the corresponding ketoamide (IV-2). Hydroxyamides containing cyclic
ethers, cyclic sulfones or cyclic amides can be oxidized to the
corresponding ketoamides using an oxidative reagent such as DMP or
IBX. For hydroxyamides containing a thioether, a stoichiometric
amount of Pd/C or copper(II) acetate is added to avoid oxidation of
the thioether to the corresponding sulfoxide. The Boc group can be
deprotected using HCl to give the amino ketoamides (IV-3,
B-C-D).
##STR00030##
Method V: Synthesis of Product Ketoamides (V-1, B-C-D to
A-B-C-D)
[0745] The B-C-D amino ketoamide (IV-3) can be coupled with
carboxylic acid, acid chloride, sulfonyl chloride or isocyanate
using standard procedures to form the amide linked, sulfonamide
linked or urea linked ketoamide (V-1, A-B-C-D).
##STR00031##
Method VI: Synthesis of Product Ketoamides (VI-2, A-B-C to
A-B-C-D)
[0746] Triazoloproline carboxylic acid (III-3, A-B-C) can be
coupled to the amino hydroxyamide (I-6, D) using standard amide
coupling conditions to afford the corresponding hydroxyamide
(VI-1), which can be oxidized as described in Method IV to afford
the ketoamide (VI-2, A-B-C-D).
##STR00032##
Method VII: Synthesis of Hydroxyprolines (VII-5, A-B-C-D)
[0747] 4-Hydroxyproline methyl ester can be coupled with a
protected amino acid using standard amide coupling procedures to
provide the corresponding Boc protected hydroxyproline ester
(VII-1, B-C). The protecting group can be cleaved using standard
deprotection methods (e.g. for a Boc, deprotection can be
accomplished via HCl) and the resulting amino ester can be reacted
with acid chloride or carboxylic acid using standard conditions to
afford the hydroxyproline esters (VII-2, A-B-C). The ester is
hydrolyzed using basic protocols such as LiOH or NaOH in THF/MeOH
to provide the carboxylic acid (VII-3), which is then coupled with
aminoheterocyclic 2-hydroxyacetamide (I-6, D) to provide the
hydroxyamide (VII-4). Oxidation of the hydroxyamide as described in
Method IV provides the hydroxyproline ketoamide (VII-5,
A-B-C-D).
##STR00033##
Method VIII: Synthesis of Heterocyclic Substituted Prolines (VIII-1
and VIII-2, A-B-C-D)
[0748] The hydroxyproline ketoamides (VII-5) can be coupled with
various heteroaromatics or hydroxyl heteroaromatics via standard
Mitsunobu conditions such as DEAD/Ph.sub.3P to provide the
corresponding 4-heteroaromatic and heteroaromatic ether proline
derivatives (VIII-1) and (VIII-2), respectively (A-B-C-D).
##STR00034##
Method IX: Synthesis of Ketoproline Prolines (IX-1, A-B-C-D)
[0749] The hydroxyproline ketoamides (VII-5) can be oxidized using
standard oxidation procedures such as DMP to provide the
corresponding 4-ketoproline derivative (IX-1, A-B-C-D).
##STR00035##
Method X: Synthesis of Aryl/Heteroaryl Prolines (X-3, A-B-C-D)
[0750] The ketoprolines (IX-1) is converted to the enol triflate
(X-1) using triflic anhydride in the presence of base. This enol
triflate can be coupled to form the aryl or heteroaryl proline
(X-2) using standard cross-coupling conditions, such as palladium
catalysis with the corresponding aryl or heteroaryl boronic acid.
The resulting olefin can be selectively reduced using
RhCl(PPh.sub.3).sub.3 (Wilkinson's catalyst) to provide the aryl or
heteroaryl proline derivative (X-3, A-B-C-D).
##STR00036##
Method XI: Synthesis of Heterocyclic Boronic Acids (XI-5,
A-B-C-D)
[0751] The sulfonamides (XI-1) can be prepared from the
corresponding ketone using the method of Nitta, A., et al. Bioorg.
Med. Chem. Lett. 2008, 18, 5435. This sulfonamide is converted to
the corresponding boronate ester (XI-2) using the method of Ellman,
J., et al. J. Org. Chem. 2014, 79, 3671. The sulfonamide group is
deprotected using standard procedures such as HCl to afford the
amino boronate ester (XI-3). The amino boronate is coupled to a
carboxylic acid (A-B-C-OH) using standard amide coupling procedures
to afford the fully elaborated boronate ester (XI-4). Deprotection
of the boronate ester using standard acidic methods such as
HCl/isobutane boronic acid gives the corresponding boronic acid
(XI-5, A-B-C-D).
##STR00037##
Preparation of Intermediates
Intermediate A: benzyl
4-amino-4-(2-amino-1-hydroxy-2-oxoethyl)piperidine-1-carboxylate
Hydrochloride
##STR00038##
[0752] Step 1: Preparation of benzyl
4-((tert-butoxycarbonyl)amino)-4-(methoxy(methyl)carbamoyl)piperidine-1-c-
arboxylate (1)
[0753] To a solution of
1-((benzyloxy)carbonyl)-4-((tert-butoxycarbonyl)amino)piperidine-4-carbox-
ylic acid (AstaTech, PA, catalog #66729) (4.5 g, 11.9 mmol) in DMA
(22 mL) was added EDC (3.4 g, 17.8 mmol), HOAt (0.6 M in DMF, 3.96
mL, 2.38 mmol), N,O-dimethyl hydroxylamine hydrochloride (2.32 g,
23.8 mmol) and diisopropylethylamine (6.2 mL, 35.7 mmol). The
reaction mixture was stirred at 35.degree. C. for 3 hours at which
point additional quantities of diisopropylethylamine (3.1 mL, 17.9
mmol), and EDC (152 mg, 0.79 mmol) were added and the mixture was
stirred at 35.degree. C. for an additional 2 hours. The mixture was
then diluted with water (100 mL) and sat. aq. NH.sub.4Cl (100 mL)
and extracted with EtOAc (2.times.200 mL). The combined extracts
were washed with sat. aq. NaHCO.sub.3 (50 mL) and concentrated
under reduced pressure. The resulting residue was purified by
column chromatography using a RediSep cartridge (120 g, silica gel)
eluting with a 0-60% EtOAc in hexanes gradient. The fractions were
monitored by TLC using EtOAc/DCM (3/7). The desired fractions were
concentrated under reduced pressure to give the title compound.
Step 2: Preparation of benzyl
4-((tert-butoxycarbonyl)amino)-4-formylpiperidine-1-carboxylate
(2)
[0754] To a 250 mL round bottom flask charged with LAH (275 mg,
7.24 mmol) was added THF (30 mL) and the suspension was cooled to
-78.degree. C. in a dry ice/acetone bath for 5 minutes. This
suspension was treated with a solution of compound 1 (3.05 g, 7.24
mmol) in THF (60 mL) via an addition funnel and the resulting
mixture was stirred at -78.degree. C. After 2 hours, the reaction
mixture was quenched with a solution of 10% aq. NaHSO.sub.4 hydrate
(22 mL) dropwise over a period of 10 minutes. The cooling bath was
removed and the mixture was stirred at 23.degree. C. After 14
hours, the mixture was concentrated under reduced pressure and the
resulting aqueous mixture was extracted with Et.sub.2O (2.times.100
mL). The combined extracts were washed with 0.1 N HCl (100 mL) and
then sat. aq. NaHCO.sub.3 (50 mL). This solution was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. The
resulting residue was purified by column chromatography using a
RediSep cartridge (120 g, silica gel) eluting with a 0-100% EtOAc
in hexanes gradient. The desired fractions were concentrated under
reduced pressure to provide the title compound.
Step 3: Preparation of benzyl
4-((tert-butoxycarbonyl)amino)-4-(cyano(hydroxy)methyl)
piperidine-1-carboxylate (3)
[0755] To a solution of compound 2 (2.31 g, 6.38 mmol) in dioxane
(24 mL) cooled to 0.degree. C. in an ice bath was added 40% aq.
NaHSO.sub.3 (6.07 mL, 23.6 mmol) over a period of 10 minutes. The
stirring was continued for an additional 10 minutes and the
resulting mixture was treated with a solution of KCN (1.54 g, 23.6
mmol) in water (8.7 mL). This mixture was stirred for an additional
30 minutes and then the cooling bath was removed and the mixture
was stirred at 23.degree. C. After 2 hours, the mixture was
extracted with EtOAc (100+75 mL). The combined extracts were washed
with sat. aq. NaHCO.sub.3, dried over MgSO.sub.4, filtered and
concentrated under reduced pressure to provide the title
compound.
Step 4: Preparation of benzyl
4-(2-amino-1-hydroxy-2-oxoethyl)-4-(tert-butoxycarbonyl)amino)piperidine--
1-carboxylate (4)
[0756] To a solution of compound 3 (1.0 g, 2.57 mmol) in DMSO (8
mL) and water (2.5 mL) cooled to 0.degree. C. in an ice bath was
added K.sub.2CO.sub.3 (177 mg, 1.28 mmol) and the mixture was
stirred for 10 minutes. To this mixture was added urea hydrogen
peroxide (1.21 g, 12.85 mmol) portionwise over 15 minutes. This
mixture was stirred at 0.degree. C. for another 10 minutes and then
warmed to 23.degree. C. After 6 hours, the mixture was diluted with
water (50 mL) and extracted with EtOAc (2.times.50 mL). The
combined extracts were washed with 10% aq. Na.sub.2S.sub.2O.sub.3
(10 mL) and then brine (20 mL). The organic layer was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. This
oil was purified by column chromatography using a RediSep cartridge
(400 g, silica gel) eluting with a 0-10% MeOH in DCM gradient. The
desired fractions were concentrated under reduced pressure to
provide the title compound.
Step 5: Preparation of benzyl
4-amino-4-(2-amino-1-hydroxy-2-oxoethyl)piperidine-1-carboxylate
Hydrochloride
[0757] To a solution of compound 4 (200 mg, 0.49 mmol) in MeOH (2
mL) was added 4 M HCl in dioxane (2 mL, 8 mmol) and the mixture was
allowed to stand at 23.degree. C. After 1 hour, the mixture was
concentrated under reduced pressure to provide the title
compound.
Intermediate B:
2-(4-aminotetrahydro-2H-pyran-4-yl)-2-hydroxyacetamide
##STR00039##
[0758] Step 1: Preparation of tert-butyl
(4-formyltetrahydro-2H-pyran-4-yl)carbamate (5)
[0759] To a solution of tert-butyl
(4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl)carbamate (PharmaBlock,
CN, catalog #PBU0380) (8.0 g, 34.6 mmol) in DCM (100 mL) under
nitrogen and cooled to 0.degree. C. in an ice bath was added
Dess-Martin periodinane (16.1 g, 38 mmol) and NaHCO.sub.3 (4.4 g,
51.9 mmol). The resulting white suspension was stirred at 0.degree.
C. The reaction was monitored by TLC (hexanes/EtOAc 8:2) and after
1.5 hours was quenched with sat. aq. Na.sub.2S.sub.2O.sub.3 (100
mL) and stirred at 23.degree. C. After 1 hour, the white solid was
filtered through celite and the filter pad was washed with DCM
(2.times.50 mL). The filtrates were partitioned and the organic
layer was dried over MgSO.sub.4, filtered and concentrated under
reduced pressure to provide the title compound.
Step 2: Preparation of tert-butyl
(4-(cyano(hydroxy)methyl)tetrahydro-2H-pyran-4-yl)carbamate (6)
[0760] A solution of compound 5 (34.6 mmol) in dioxane (80 mL) was
cooled to 0.degree. C. in an ice bath and KCN (4.5 g, 69 mmol) was
added followed by 40% aq. NaHSO.sub.3 (18 mL, 69 mmol). After
stirring at 0.degree. C. for 1 hour, the cooling bath was removed
and the reaction was allowed to stir at 23.degree. C. After 18
hours, the mixture was diluted with water (100 mL) and extracted
with EtOAc (3.times.75 mL). The combined extracts were washed with
brine (75 mL), dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. This residue was purified by column
chromatography using a RediSep cartridge (120 g, silica gel)
eluting with a 5-60% EtOAc in hexanes gradient. The desired
fractions were concentrated under reduced pressure to provide the
title compound as a white solid.
Step 3: Preparation of
2-(4-aminotetrahydro-2H-pyran-4-yl)-2-hydroxyacetamide
[0761] To a solution of compound 6 (3.80 g, 17.8 mmol) in dioxane
(10 mL) was added 4 M HCl in dioxane (20 mL, 80 mmol) and the
reaction mixture was stirred at 23.degree. C. After 18 hours, the
mixture was concentrated under reduced pressure and the residue was
dried under high vacuum to provide the Boc deprotected crude
intermediate. This yellow solid was dissolved in conc. HCl (50 mL)
and stirred at 23.degree. C. The reaction was monitored by LC-MS.
After 6 hours, the mixture was concentrated under reduced pressure
and the residue was further azeotroped with MeOH to remove residual
water and HCl. This residue was dissolved in MeOH (10 mL) and
treated with 1 M aq. NaOH to pH >10. The reaction mixture was
concentrated under reduced pressure and the residue was purified by
column chromatography using a RediSep cartridge (100 g, silica gel)
eluting with a 0-25% MeOH in DCM gradient containing 0.1% TEA. The
fractions were monitored by TLC using MeOH:DCM (8:2) visualized by
KMnO.sub.4 stain. The desired fractions were concentrated under
reduced pressure to provide the title compound as a white foam.
Intermediate C: 2-(3-aminotetrahydrofuran-3-yl)-2-hydroxyacetamide
Hydrochloride
##STR00040##
[0762] Step 1: Preparation of tert-butyl
(3-formyltetrahydrofuran-3-yl)carbamate (7)
[0763] The title compound was prepared in a similar manner to
compound 5 using tert-butyl
(3-(hydroxymethyl)tetrahydrofuran-3-yl)carbamate (PharmaBlock
catalog #PB05450).
Step 2: Preparation of tert-butyl
(3-(cyano(hydroxy)methyl)tetrahydrofuran-3-yl)carbamate (8)
[0764] The title compound was prepared in a similar manner to
compound 6 using compound 7.
Step 3: Preparation of tert-butyl
(3-(2-amino-1-hydroxy-2-oxoethyl)tetrahydrofuran-3-yl)carbamate
(9)
[0765] The title compound was prepared in a similar manner to
compound 4 using compound 8.
Step 4: Preparation of
2-(3-aminotetrahydrofuran-3-yl)-2-hydroxyacetamide
Hydrochloride
[0766] The title compound was prepared in a similar manner to
Intermediate A using compound 9.
Intermediate D: 2-(4-aminooxepan-4-yl)-2-hydroxyacetamide
Hydrochloride
##STR00041##
[0767] Step 1: Preparation of tert-butyl
(4-(hydroxymethyl)oxepan-4-yl)carbamate (10)
[0768] To a solution of (4-aminooxepan-4-yl)methanol hydrochloride
(Enamine catalog #2015-0049381A) (1.1 g, 6.06 mmol) in DMF (7 mL)
was added Boc.sub.2O (1.6 g, 7.27 mmol) and TEA (1.7 mL, 12.1 mmol)
and the reaction mixture was stirred at 23.degree. C. After 2
hours, the mixture was treated with imidazole (50 mg) to quench
residual anhydride and then partitioned between water (20 mL) and
EtOAc (20 mL). The aqueous layer was extracted with EtOAc (20 mL).
The combined organic extracts were washed with 1 M HCl (20 mL),
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to provide the title compound.
Steps 2-5: Preparation of 2-(4-aminooxepan-4-yl)-2-hydroxyacetamide
Hydrochloride
[0769] The title compound was prepared in a similar manner to
Intermediate C using compound 10.
Intermediate E:
2-(4-aminotetrahydro-2H-thiopyran-4-yl)-2-hydroxyacetamide
##STR00042##
[0770] Step 1: Preparation of tert-butyl
(4-(methoxy(methyl)carbamoyl)tetrahydro-2H-thiopyran-4-yl)carbamate
(14)
[0771] To a solution of
4-((tert-butoxycarbonyl)amino)tetrahydro-2H-thiopyran-4-carboxylic
acid (Oakwood Products, SC, catalog #300359) (20.5 g, 78.5 mmol) in
DMA (200 mL) was added HATU (35.8 g, 94.1 mmol) and the reaction
mixture was stirred at 23.degree. C. After 5 minutes, the mixture
was cooled to 0.degree. C. in an ice bath and treated with
iPr.sub.2EtN (13.7 mL, 78.5 mmol) and stirred for 5 minutes. After
this time, N,O-dimethyl hydroxylamine hydrochloride (15.3 g, 157
mmol) and additional iPr.sub.2EtN (27.3 mL, 157 mmol) were added
and the reaction mixture was stirred at 23.degree. C. After 20
hours, water (500 mL) was added and the mixture was extracted with
EtOAc (2.times.500 mL). The combined extracts were washed with 1 M
aq. HCl (100 mL) and then sat. aq. NaHCO.sub.3 (200 mL), dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. This
residue was purified by column chromatography using a RediSep
cartridge (330 g, silica gel) eluting with a 0-100% EtOAc in
hexanes gradient. The fractions were monitored by TLC
(EtOAc:hexanes 1:1 visualized by KMnO.sub.4). The desired fractions
were concentrated under reduced pressure to provide the title
compound as a white solid.
Step 2: Preparation of tert-butyl
(4-formyltetrahydro-2H-thiopyran-4-yl)carbamate (15)
[0772] To a solution of compound 14 (3.05 g, 7.24 mmol) in THF (200
mL) cooled to -78.degree. C. in a dry ice/acetone bath was added
LAH (1.41 g, 37.1 mmol) portionwise over a period of 10 minutes.
After the addition was complete, the dry ice/acetone bath was
removed and the mixture was stirred at 0.degree. C. in an ice bath.
After 30 minutes, the mixture was cooled to -78.degree. C. in a dry
ice/acetone bath and a solution of NaHSO.sub.3.H.sub.2O (5.12 g,
37.1 mmol) in water (36.9 mL) was carefully added at such a rate to
maintain the internal temperature below -50.degree. C. After the
addition was complete, the dry ice/acetone bath was exchanged for
an ice bath and the mixture was stirred for 20 minutes followed by
removal of the ice bath and stirring at 23.degree. C. for 30
minutes. To this suspension was added Et.sub.2O (200 mL) and the
stirring was continued. After 20 minutes, this suspension was
filtered through celite and the plug was washed with EtOAc (200
mL). The combined filtrates were washed with brine (50 mL), dried
over MgSO.sub.4, filtered and concentrated under reduced pressure.
The resulting residue was purified by column chromatography using a
RediSep cartridge (120 g, silica gel) eluting with a 0-100% EtOAc
in hexanes gradient. The desired fractions were concentrated under
reduced pressure to provide the title compound.
Step 3: Preparation of tert-butyl
(4-(cyano(hydroxy)methyl)tetrahydro-2H-thiopyran-4-yl)carbamate
(16)
[0773] To a solution of compound 15 (5.39 g, 22.0 mmol) in dioxane
(65 mL) cooled to 0.degree. C. in an ice bath for 3 minutes was
added a solution of 40% aq. NaHSO.sub.4.H.sub.2O (22.6 mL, 87.9
mmol) and the solution was stirred for 15 minutes. To this mixture
was added a solution of KCN (5.7 g, 87.9 mmol) in water (33 mL) and
the mixture was stirred at 0.degree. C. for 10 minutes and then at
23.degree. C. for 18 hours. This solution was partitioned between
EtOAc (40 mL) and brine (40 mL) and the aqueous layer was extracted
with EtOAc (100 mL). The combined extracts were dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
provide the title compound.
Step 4: Preparation of
2-(4-aminotetrahydro-2H-thiopyran-4-yl)-2-hydroxyacetamide
[0774] The title compound was prepared in a similar manner as
Intermediate B, step 3 using compound 16 (6.79 g, 22 mmol), and
obtained as a white solid.
Intermediate F:
2-(3-aminotetrahydrothiophen-3-yl)-2-hydroxyacetamide
##STR00043##
[0775] Step 1: Preparation of
3-((tert-butoxycarbonyl)amino)tetrahydrothiophene-3-carboxylic Acid
(17)
[0776] To a solution of 3-aminotetrahydrothiophene-3-carboxylic
acid hydrochloride (J&W PharmLab, PA, catalog #78301265) (3.0
g, 16.3 mmol) in dioxane (150 mL) was added 1 M aq. NaOH (48.9 mL,
48.9 mmol) and Boc.sub.2O (7.13 g, 32.6 mmol) and the reaction
mixture was stirred at 23.degree. C. After 3 days, the mixture was
acidified (pH=1-2) with 1 M aq. HCl (50 mL, 50 mmol) and extracted
with EtOAc (2.times.100 mL). The combined extracts were
concentrated under reduced pressure and purified by column
chromatography using a RediSep cartridge (40 g, silica gel) eluting
with a 20-100% EtOAc in hexanes gradient. The desired fractions
were concentrated under reduced pressure to provide the title
compound as a white solid.
Steps 2-5: Preparation of
2-(3-aminotetrahydrothiophen-3-yl)-2-hydroxyacetamide
[0777] The title compound was prepared in a similar manner to
Intermediate E, steps 1-4, starting with compound 17.
Intermediate G:
2-(3-aminotetrahydro-2H-thiopyran-3-yl)-2-hydroxyacetamide
Hydrochloride
##STR00044##
[0778] Step 1: Preparation of
3-((tert-butoxycarbonyl)amino)tetrahydro-2H-thiopyran-3-carboxylic
acid (21)
[0779] The title compound was prepared in a similar manner to
compound 10 using 3-aminotetrahydro-2H-thiopyran-3-carboxylic acid
hydrochloride.
Step 2: Preparation of tert-butyl
(3-(methoxy(methyl)carbamoyl)tetrahydro-2H-thiopyran-3-yl)carbamate
(22)
[0780] The title compound was prepared in a similar manner to
compound 14 using compound 21.
Step 3: Preparation of
tert-butyl(3-formyltetrahydro-2H-thiopyran-3-yl)carbamate (23)
[0781] The title compound was prepared in a similar manner to
compound 15 using compound 22.
Step 4: Preparation of tert-butyl
(3-(cyano(hydroxy)methyl)tetrahydro-2H-thiopyran-3-yl)carbamate
(24)
[0782] The compound was prepared in similar manner to compound 16
using compound 23.
Step 5: Preparation of tert-butyl
(3-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-thiopyran-3-yl)carbamate
(25)
[0783] The title compound was prepared in a similar manner to
compound 4 using compound 24.
Step 6: Preparation of
2-(3-aminotetrahydro-2H-thiopyran-3-yl)-2-hydroxyacetamide
Hydrochloride
[0784] The title compound was prepared in a similar manner to
Intermediate A, step 5, using compound 25.
Intermediate H:
(2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic
Acid
##STR00045##
[0785] Step 1: Preparation of 1-(tert-butyl) 2-methyl
(2S,4R)-4-((methylsulfonyl)oxy) pyrrolidine-1,2-dicarboxylate
(26)
[0786] Into a 2 L round-bottom flask equipped with a large stir bar
and under nitrogen was added 1-(tert-butyl) 2-methyl
(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (100.0 g, 0.4 mol)
and DCM (800 mL). The solution was cooled to 0.degree. C. in an ice
bath and triethylamine (182 g, 1.8 mol) was added in a single
portion, followed by drop-wise addition of methanesulfonyl chloride
(103 g, 0.9 mol). The resulting mixture was stirred at 0.degree. C.
for 1 hour and then warmed to 23.degree. C. and stirred for 18
hours. TLC analysis revealed complete conversion of the alcohol
starting material. The reaction was quenched by pouring the mixture
into water (2.0 L) and the mixture was extracted with DCM
(3.times.1.0 L). The combined organic extracts were washed with
sat. aq. NaHCO.sub.3 (1.0 L), water (1.0 L) and brine (1.0 L),
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure to afford the title compound. This yellow oil (130 g) was
used directly in the next step without further purification.
Step 2: Preparation of 1-(tert-butyl) 2-methyl
(2S,4S)-4-azidopyrrolidine-1,2-dicarboxylate (27)
[0787] Into a 3 L round-bottom flask equipped with a magnetic stir
bar and under nitrogen was added compound 26 (143 g, 442 mmol),
sodium azide (53 g, 804 mmol) and DMF (900 mL). The solution was
heated to 70.degree. C. for 18 hours. The reaction mixture was
cooled to 23.degree. C. and poured into water (2.0 L) and extracted
with MTBE (3.times.1 L). The combined organic extracts were washed
with water (5.times.1.0 L), brine (2.times.1.0 L), dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
afford the title compound as an oil (98 g).
Step 3: Preparation of 1-(tert-butyl) 2-methyl
(2S,4S)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-1,2-
-dicarboxylate (28)
[0788] A solution of compound 27 (43 mL, 440 mmol, 2.0 equiv),
Cp*RuCl(PPh.sub.3).sub.2 (Strem catalog #44-0117) (8.8 g, 11 mmol,
0.05 equiv) and 1,4-dioxane (500 mL) were charged into a 1 L
round-bottom flask. The solution was bubbled with a steady flow of
nitrogen for 1 hour, and the reaction mixture changed color from
yellow to deep brown. The reaction mixture was heated to 70.degree.
C. for 15 hours and then cooled to 23.degree. C. The mixture was
concentrated under reduced pressure to remove the bulk of the
dioxane and the resulting oil was loaded directly onto a silica gel
column (1 kg) and purified by column chromatography, eluting with a
2-4% MeOH in DCM gradient to afford the title compound as a brown
oil (67 g).
Step 4: Preparation of methyl
(2S,4S)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-c-
arboxylate Hydrochloride (29)
[0789] Compound 28 (98 g, 277 mmol), MeOH (400 mL) and methanolic
HCl solution (approx. 3.0 M, 800 mL) were added to a 3 L
round-bottom flask equipped with a magnetic stir bar. The reaction
mixture was stirred at 23.degree. C. for 12 hours at which point
TLC analysis revealed complete conversion of starting material. The
reaction mixture was concentrated under reduced pressure and dried
under vacuum to remove any trace methanol or HCl residues. The
resulting brown solid was used directly in the next step without
further purification (90 g).
Step 5: Preparation of methyl
(2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylate
(30)
[0790] Into a 3 L round-bottom flask equipped with a magnetic stir
bar was added compound 29 (70 g, 241 mmol),
(R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (70
g, 258 mmol), HATU (110 g, 289 mmol), DCM (600 mL) and DMF (400
mL). The reaction mixture was treated with iPr.sub.2EtN (126 g, 973
mmol) dropwise over 30 minutes and the mixture was stirred at
23.degree. C. for 12 hours affording a deep brown solution. The
reaction mixture was diluted with EtOAc (1.0 L) and washed with 1 M
aq. HCl (3.times.400 mL), brine (3.times.300 mL), dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford
an oil. The residue was purified by column chromatography through
silica gel (1 kg), eluting with a 2-4% MeOH in DCM gradient to
afford the title compound as a light brown solid (77 g).
Step 6: Preparation of
(2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic
Acid
[0791] To a mixture of compound 30 (10.9 g, 21.5 mmol) in THE (43
mL) and MeOH (23 mL) was added 1 M aq. LiOH (87 mL, 86 mmol) and
the reaction mixture was stirred at 23.degree. C. for 1.5 hours.
This mixture was treated with 1 M aq. HCl (86 mL) and concentrated
under reduced pressure to provide the title compound.
Intermediate I:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic Acid
##STR00046##
[0792] Step 1: Preparation of 1-(tert-butyl) 2-methyl
(2S,4R)-4-((methylsulfonyl)oxy) pyrrolidine-1,2-dicarboxylate
(31)
[0793] To a solution of 1-(tert-butyl) 2-methyl
(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (13.2 g, 53.8 mmol)
in DCM (110 mL) cooled to 0.degree. C. in an ice bath was added TEA
(17 mL, 236.8 mmol) and MsCl (9.2 mL, 118.4 mmol). The reaction was
allowed to warm to 23.degree. C. and stirred for 18 hours. After
this time, the reaction mixture was diluted with DCM and washed
with aq. NaHCO.sub.3, water and brine. The organic layer was dried
over MgSO.sub.4, filtered and concentrated under reduced pressure
to provide the title compound.
Step 2: Preparation (2S,4S)-1-tert-butyl 2-methyl
4-azidopyrrolidine-1,2-dicarboxylate (32)
[0794] A suspension of compound 31 (20 g, 53.8 mmol) and NaN.sub.3
(7.0 g, 107.6 mmol) in DMF (110 mL) was stirred at 75.degree. C.
After 24 hours, the mixture was allowed to cool to 23.degree. C.
and diluted with water and extracted with EtOAc (3.times.100 mL).
The combined extracts were washed with brine, dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. This
residue was purified by column chromatography using a RediSep
cartridge (80 g, silica gel) eluting with a 0-20% EtOAc in hexanes
gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound.
Step 3: Preparation of methyl
(2S,4S)-4-azidopyrrolidine-2-carboxylate Hydrochloride (33)
[0795] To a solution of compound 32 (14.5 g, 53.8 mmol) in MeOH
(135 mL) was added 36% aq. HCl (19 mL, 188.3 mmol) and the reaction
mixture was stirred at 23.degree. C. After 18 hours, the mixture
was concentrated under reduced pressure and the residue azeotroped
with MeOH (3.times.50 mL) to provide the title compound.
Step 4: Preparation of methyl
(2S,4S)-4-azido-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropano-
yl)pyrrolidine-2-carboxylate (34)
[0796] A suspension of compound 33 (12.8 g, 47 mmol) and HATU (17.9
g, 47 mmol) in DCM (110 mL) was stirred for 10 minutes and then
methyl (2S,4S)-4-azidopyrrolidine-2-carboxylate hydrochloride (9.73
g, 47 mmol) and iPr.sub.2EtN (20.5 mL, 118 mmol) were added and the
reaction mixture was stirred at 23.degree. C. After 18 hours, the
mixture was partitioned with 1 M aq. HCl (200 mL). The aqueous
layer was extracted with DCM (3.times.100 mL). The combined organic
extracts were washed with brine, dried over MgSO.sub.4, filtered
and concentrated under reduced pressure. This residue was purified
by column chromatography using a RediSep cartridge (120 g, silica
gel) eluting with a 0-50% EtOAc in hexanes gradient. The fractions
were monitored by TLC (EtOAc/hexanes (3/7) visualized by ninhydrin
staining). The desired fractions were concentrated under reduced
pressure to provide the title compound.
Step 5: Preparation of methyl
(2S,4S)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-azidopyrrolidine-2-carbox-
ylate Hydrochloride (35)
[0797] The title compound was prepared in a similar manner as
compound 29 using compound 34.
Step 6: Preparation of methyl
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-azidopyrrolidin-
e-2-carboxylate (36)
[0798] To a suspension of compound 35 (10.4 g, 29 mmol) and
2-naphthoyl chloride (6.1 g, 31.9 mmol) in DCM (150 mL) was added
iPr.sub.2EtN (12.6 mL, 72.5 mmol) and the reaction mixture was
stirred at 23.degree. C. After 6 hours, the mixture was partitioned
between 1 M aq. HCl (100 mL) and DCM (100 mL). The aqueous layer
was extracted with DCM (2.times.100 mL). The combined extracts were
washed with water, dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. This residue was purified by column
chromatography using a RediSep cartridge (330 g, silica gel)
eluting with a 0-50% EtOAc in hexanes gradient. The desired
fractions were concentrated under reduced pressure to provide the
title compound.
Step 7: Preparation of methyl
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylate (37)
[0799] To a 40 mL scintillation vial was added compound 36 (2.5 g,
5.2 mmol), 2-methylbut-3-yn-2-ol (1.74 g, 20.8 mmol),
pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II)
chloride (199 mg, 0.26 mmol) and dioxane (26 mL). This mixture was
stirred at 64.degree. C. under nitrogen for 3 hours. After this
time, this mixture was purified by column chromatography using a
RediSep cartridge (40 g, silica gel) eluting with EtOAc. The
desired fractions were concentrated under reduced pressure to
provide the title compound.
Step 8: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic Acid
[0800] To a solution of compound 37 (2.9 g, 5.3 mmol) in MeOH (25
mL) and THF (25 mL) was added 1 M aq. LiOH (26 mL, 26 mmol) and the
mixture was stirred at 23.degree. C. After 1 hour, the mixture was
concentrated under reduced pressure and the resulting residue was
dissolved in THF (30 mL) and acidified to pH=1 with 1 M aq. HCl.
This mixture was further diluted with water and extracted with
EtOAc (3.times.20 mL). The combined extracts were dried over
MgSO.sub.4, filtered and concentrated under reduced pressure to
provide the title compound.
Intermediate J:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-ami-
no-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-y-
l)pyrrolidine-2-carboxamide Hydrochloride
##STR00047##
[0801] Step 1: Preparation of tert-butyl
(2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-pyran-4-
-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidi-
n-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (38)
[0802] To a suspension of
(2S,4S)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-(5-
-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxylic
acid (Intermediate H, 21.7 g, 44 mmol) and HATU (20 g, 53 mmol) in
DCM (220 mL) was added Intermediate B (10.2 g, 48.4 mmol) and
iPr.sub.2EtN (34.5 mL, 198 mmol) and the yellow solution was
stirred at 23.degree. C. After 18 hours, sat. aq. NaHCO.sub.3 was
added and the aqueous layer was extracted with DCM (4.times.100
mL). The combined extracts were dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. The residue was purified by
column chromatography using a RediSep cartridge (330 g, silica gel)
eluting with a 0-15% MeOH in DCM gradient. The desired fractions
were concentrated under reduced pressure to provide the title
compound as a white solid.
Step 2: Preparation of tert-butyl
((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)carba-
moyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-
-cyclohexyl-1-oxopropan-2-yl)carbamate (39)
[0803] To a solution of compound 38 (7.5 g, 11.6 mmol) in DMSO (60
mL) was added IBX (45% by weight, 14.4 g, 23.1 mmol) and the
reaction mixture was stirred at 23.degree. C. After 6 hours,
additional IBX (2.1 g, 3.4 mmol) was added and the reaction mixture
was stirred at 23.degree. C. for a further 18 hours. The mixture
was quenched with 10% aq. Na.sub.2S.sub.2O.sub.3 (65 mL, 17.4 mmol)
and extracted with EtOAc (3.times.50 mL). The combined extracts
were washed with sat. aq. NaHCO.sub.3, brine (1.times.), dried,
filtered and concentrated under reduced pressure. This residue was
purified by column chromatography using a RediSep cartridge (330 g,
silica gel) eluting with a 0-7.5% MeOH in DCM gradient. The desired
fractions were concentrated under reduced pressure to provide the
title compound as a white solid.
Step 3: Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-2-ami-
no-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-y-
l)pyrrolidine-2-carboxamide Hydrochloride
[0804] To a solution of compound 39 (3.45 g, 5.33 mmol) in MeOH (27
mL) was added 36% aq. HCl (2.6 mL, 26.7 mmol) and the mixture was
stirred at 23.degree. C. After 18 hours, the mixture was
concentrated under reduced pressure to provide the title
compound.
Intermediate K:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-2-amino-3-cyclohex-
ylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-
-2-carboxamide Hydrochloride
##STR00048##
[0806] The title compound was prepared in a similar manner to
Intermediate J using Intermediate D.
Intermediate L:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-
-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-
-1-yl)pyrrolidine-2-carboxamide Hydrochloride
##STR00049##
[0807] Step 1: Preparation of tert-butyl
((2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)tetrahydro-2H-thiopy-
ran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrr-
olidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (42)
[0808] The title compound was prepared in a similar manner to
compound 38 using Intermediate E, where DMF was used in place of
DCM as the solvent.
Step 2: Preparation of tert-butyl
((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)c-
arbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-y-
l)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (43)
[0809] To a solution of compound 42 (5.0 g, 7.51 mmol) in DCM (150
mL) was added copper (II) acetate hydrate (0.75 g, 3.75 mmol) and
the reaction mixture was stirred at 23.degree. C. for 30 minutes.
DMP (3.82 g, 9.0 mmol) was added and the reaction mixture was
stirred at 23.degree. C. The reaction was monitored by LC-MS and
additional DMP (3.82 g, 9.0 mmol) was added portionwise. After 4
hours, the reaction mixture was washed with 10% aq.
Na.sub.2S.sub.2O.sub.3 (3.times.30 mL). The resulting organic layer
was washed with 1 M disodium EDTA (2.times.20 mL), dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. This
residue was purified by column chromatography using a RediSep
cartridge (120 g, silica gel) eluting with a 2.5-15% MeOH in DCM
gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound as a white solid.
Step 3: Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-
-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-
-1-yl)pyrrolidine-2-carboxamide Hydrochloride
[0810] To a solution of compound 43 (2.37 g, 3.57 mmol) in MeOH (7
mL) was added 4 M HCl in dioxane (7.1 mL, 28.5 mmol) and the
reaction mixture was stirred at 23.degree. C. After 2 hours, the
mixture was concentrated under reduced pressure. The resulting
solid was dissolved in THF and concentrated under reduced pressure
to provide the title compound.
Intermediate M:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1-
,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride
##STR00050##
[0811] Step 1: Preparation of tert-butyl
((2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)-1,1-dioxidotetrahyd-
ro-2H-thiopyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triaz-
ol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate
(44)
[0812] To a solution of compound 42 (9.5 g, 14.3 mmol) in DCM (250
mL) was added mCPBA (70 wt %, 8.8 g, 35.7 mmol) and the reaction
mixture was stirred at 23.degree. C. After 1 hour, the mixture was
partitioned between 10% aq. Na.sub.2S.sub.2O.sub.3 (10 mL), sat.
aq. NaHCO.sub.3 (100 mL) and DCM (300 mL). The aqueous layer was
extracted with DCM (400 mL). The combined extracts were washed with
water (100 mL), dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. This residue was purified by column
chromatography using a RediSep cartridge (330 g, silica gel)
eluting with a 0-15% MeOH in DCM gradient. The desired fractions
were concentrated under reduced pressure to provide the title
compound.
Step 2: Preparation of tert-butyl
((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thio-
pyran-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)py-
rrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)carbamate (45)
[0813] To a solution of compound 44 (6.97 g, 10 mmol) in DCM (200
mL) was added NaHCO.sub.3 (882 mg, 10.5 mmol) and DMP (4.45 g, 10.5
mmol) and the reaction mixture was stirred at 23.degree. C. After 2
hours, the mixture was quenched with 10% aq. Na.sub.2S.sub.2O.sub.3
(5 mL), diluted with water (75 mL) and extracted with DCM
(2.times.300 mL). The combined extracts were washed with sat. aq.
NaHCO.sub.3 (75 mL), dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. This residue was purified by
column chromatography using a RediSep cartridge (330 g, silica gel)
eluting with a 0-15% MeOH in DCM gradient. The desired fractions
were concentrated under reduced pressure to provide the title
compound.
Step 3: Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1-
,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Hydrochloride
[0814] The title compound was prepared in a similar manner to
Intermediate L using compound 45.
PREPARATION OF EXAMPLES
Example 1: tert-butyl
4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino--
2-oxoacetyl)piperidine-1-carboxylate
##STR00051## ##STR00052##
[0815] Step 1: Preparation of Benzyl
4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino--
1-hydroxy-2-oxoethyl)piperidine-1-carboxylate (46)
[0816] The title compound was prepared in a similar manner to
Intermediate J, step 1, using Intermediate I and Intermediate
A.
Step 2: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-h-
ydroxy-2-oxoethyl)piperidin-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tri-
azol-1-yl)pyrrolidine-2-carboxamide Hydrochloride (47)
[0817] To a degassed solution of compound 46 (222 mg, 0.265 mmol)
and 1 M aq. HCl (260 .mu.L, 0.260 mmol) in MeOH (10 mL) was added
Pd(OH).sub.2 (44 mg, 0.03 mmol) and the mixture was stirred under a
balloon of H.sub.2 for 4 hours. The suspension was filtered through
celite and the filtrate was concentrated under reduced pressure to
provide the title compound.
Step 3: Preparation of tert-butyl
4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino--
1-hydroxy-2-oxoethyl)piperidine-1-carboxylate (48)
[0818] To a solution of compound 47 (128 mg, 0.173 mmol) in DMF
(0.5 mL) was added Boc.sub.2O and iPr.sub.2EtN (60 .mu.L, 0.346
mmol) and the reaction mixture was allowed to stand at 23.degree.
C. After 18 hours, water (3 mL) was added and the mixture was
extracted with EtOAc (2.times.5 mL). The combined extracts were
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. This residue was purified by column chromatography using
a RediSep cartridge (4 g, silica gel) eluting with a 0-20% MeOH in
DCM gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound.
Step 4: Preparation of tert-butyl
4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)-4-(2-amino--
2-oxoacetyl)piperidine-1-carboxylate
[0819] To a solution of compound 48 (93 mg, 0.116 mmol) in DCM (2
mL) was added DMP (64 mg, 0.15 mmol) and the reaction mixture was
stirred at 23.degree. C. After 1 hour, additional DMP (20 mg, 0.05
mmol) was added and the reaction mixture was stirred at 23.degree.
C. After 1 hour, 10% aq. Na.sub.2S.sub.2O.sub.3 (2 mL) and water (2
mL) were added and the mixture was extracted with DCM (2.times.5
mL). The combined organic extracts were dried over MgSO.sub.4,
filtered and concentrated under reduced pressure. This residue was
purified by column chromatography using a RediSep cartridge (4 g,
silica gel) eluting with a 0-20% MeOH in DCM gradient. The desired
fractions were concentrated under reduced pressure to provide the
title compound as a white solid. MS (ESI+): 801 (M+1).sup..sym.
Example 2:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-
-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1-
H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00053##
[0820] Step 1: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-h-
ydroxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-
-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (49)
[0821] To a mixture of Intermediate I (868 mg, 1.58 mmol),
Intermediate B (275 mg, 1.58 mmol) and HATU (661 mg, 1.74 mmol) in
DMF (4 mL) was added iPr.sub.2EtN (550 .mu.L, 3.16 mmol) and the
reaction mixture was stirred at 23.degree. C. After 1 hour, this
solution was partitioned between water (20 mL) and EtOAc
(2.times.50 mL). The combined extracts were washed with 1 N aq. HCl
(20 mL) and then sat. aq. NaHCO.sub.3 (20 mL). This extract was
dried over MgSO.sub.4, filtered and concentrated under reduced
pressure. This residue was purified by column chromatography using
a RediSep cartridge (80 g, silica gel) eluting with a 0-15% MeOH in
DCM gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound.
Step 2: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tr-
iazol-1-yl)pyrrolidine-2-carboxamide
[0822] To a solution of compound 49 (450 mg, 0.64 mmol) in DCM (6
mL) cooled to 0.degree. C. in an ice bath was added DMP (271 mg,
0.64 mmol). The cooling bath was removed and the mixture was
stirred at 23.degree. C. for 2 hours. To this mixture was added 10%
aq. Na.sub.2S.sub.2O.sub.3 (10 mL) and DCM (10 mL) and the reaction
mixture was stirred for 10 minutes. The resulting layers were
separated with an Isolute phase separator and the aqueous was back
extracted with DCM (10 mL) and separated. The combined extracts
were concentrated under reduced pressure and the resulting residue
was purified by column chromatography using a RediSep Gold
cartridge (24 g, silica gel) eluting with a 0-10% MeOH in DCM
gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound as a white solid. MS (ESI+):
702 (M+1).sup..sym.; .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
8.24-8.18 (1H, m), 8.00-7.83 (4H, m), 7.66-7.51 (3H, m), 5.93-5.82
(1H, m), 5.04-4.96 (1H, m), 4.78-4.60 (1H, m), 4.34-4.25 (2H, m),
3.90-3.64 (4H, m), 2.90-2.65 (2H, m), 2.20-1.94 (4H, m), 1.68 (3H,
s), 1.63 (3H, s), 1.80-1.60 (6H, m), 1.52-0.91 (7H, m) ppm.
Example 3:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1--
((R)-3-cyclohexyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydrox-
ypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00054##
[0824] To a mixture of 4-(methylsulfonyl)benzoic acid
(Combi-Blocks, CA, catalog #OR-0048) (659 mg, 3.29 mmol),
Intermediate J (1.6 g, 2.74 mmol) and HATU (1.46 g, 3.84 mmol) in
DMF (6 mL) and DCM (16 mL) was added iPr.sub.2EtN (52 .mu.L, 0.3
mmol) and the reaction mixture was stirred at 23.degree. C. for 18
hours. The mixture was partitioned between EtOAc (100 mL) and sat.
aq. NaHCO.sub.3 (100 mL) and the aqueous layer was extracted with
EtOAc (3.times.100 mL). The combined extracts were washed with
brine (100 mL), dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. This residue was purified by column
chromatography using a RediSep Gold cartridge (120 g, silica gel)
eluting with a 0-12.5% MeOH in DCM gradient. The desired fractions
were concentrated under reduced pressure to provide the title
compound as a white solid. MS (ESI+): 730 (M+1).sup..sym.
Example 4:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1--
((R)-3-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)benzamido)propanoyl)-4-(5-(-
2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00055##
[0826] To a mixture of 4-(piperidin-1-ylsulfonyl)benzoic acid
(Enamine, NJ, catalog #EN300-00395) (554 mg, 2.06 mmol),
Intermediate J (1.2 g, 2.06 mmol) and HATU (783 mg, 2.06 mmol) in
DMF (8 mL) was added iPr.sub.2EtN (360 .mu.L, 2.06 mmol) and the
reaction mixture was stirred at 23.degree. C. for 18 hours. This
mixture was partitioned between DCM (20 mL) and water (30 mL) and
separated using an Isolute phase separator. The aqueous layer was
extracted with DCM (2.times.20 mL). The organic extracts were
combined and concentrated under reduced pressure. This residue was
purified by column chromatography using a RediSep Gold cartridge
(80 g+12 g precartridge, silica gel) eluting with a 0-10% MeOH in
DCM gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound as a white solid. MS (EST+):
799 (M+1).sup..sym.; .sup.1H NMR (300 MHz, CD.sub.3OD): .delta.
8.04 (2H, d, J=8.2 Hz), 7.83 (2H, d, J=8.2 Hz), 7.55 (1H, s), 5.88
(1H, m), 4.99 (1H, m), 4.53 (1H, t, J=8.4 Hz), 4.34-4.29 (2H, m),
3.82-3.66 (4H, m), 2.99-2.96 (4H, m), 2.85 (1H, m), 2.73 (1H, m),
2.18-1.85 (4H, m), 1.78-1.71 (3H, m), 1.66 (3H, s), 1.64 (3H, s),
1.80-1.64 (6H, m), 1.44 (4H, m), 1.23-0.98 (6H, m) ppm.
[0827] The following compounds were prepared in a similar manner as
Example 3 substituting 4-(methylsulfonyl)benzoic acid with a series
of commercially available carboxylic acids. The reaction solvent
was DMF or a DMF/DCM mixture. The mixtures were purified, as in
Example 3, by column chromatography using a RediSep Gold silica gel
cartridge eluting with a 0-12.5% MeOH in DCM gradient.
Alternatively, the crude DMF mixtures were purified directly by
reverse phase column chromatography using a C18 RediSep Gold
cartridge eluting with a 0-60% ACN in water gradient containing
0.1% formic acid. The desired fractions were concentrated under
reduced pressure to provide the title compounds as white
solids.
TABLE-US-00002 Example Structure/Name MW MS (ESI+) Example 5
##STR00056## 691.78 693 (M + 1).sup..sym. Example 6 ##STR00057##
676.76 677 (M + 1).sup..sym. Example 7 ##STR00058## 702.8 703 (M +
1).sup..sym. Example 8 ##STR00059## 691.78 692 (M + 1).sup..sym.
Example 9 ##STR00060## 773.9 774 (M + 1).sup..sym. Example 10
##STR00061## 765.82 766 (M + 1).sup..sym. Example 11 ##STR00062##
772.87 773 (M + 1).sup..sym. Example 12 ##STR00063## 731.84 732 (M
+ 1).sup..sym. Example 13 ##STR00064## 731.84 732 (M + 1).sup..sym.
Example 14 ##STR00065## 767.82 768 (M + 1).sup..sym. Example 15
##STR00066## 785.81 768 (M + 1).sup..sym. Example 16 ##STR00067##
817.78 818 (M + 1).sup..sym. Example 17 ##STR00068## 709.83 710 (M
+ 1).sup..sym. Example 18 ##STR00069## 765.78 766 (M + 1).sup..sym.
Example 19 ##STR00070## 749.78 750 (M + 1).sup..sym. Example 20
##STR00071## 692.76 693 (M + 1).sup..sym. Example 21 ##STR00072##
692.76 693 (M + 1).sup..sym. Example 22 ##STR00073## 708.83 709 (M
+ 1).sup..sym. Example 23 ##STR00074## 691.77 692 (M + 1).sup..sym.
Example 24 ##STR00075## 690.79 691 (M + 1).sup..sym. Example 25
##STR00076## 690.79 691 (M + 1).sup..sym. Example 26 ##STR00077##
669.74 670 (M + 1).sup..sym. Example 27 ##STR00078## 723.82 724 (M
+ 1).sup..sym. Example 28 ##STR00079## 757.9 759 (M + 1).sup..sym.
Example 29 ##STR00080## 755.88 756 (M + 1).sup..sym. Example 30
##STR00081## 691.78 692 (M + 1).sup..sym. Example 31 ##STR00082##
692.77 693 (M + 1).sup..sym. Example 32 ##STR00083## 691.78 692 (M
+ 1).sup..sym. Example 33 ##STR00084## 691.78 692 (M + 1).sup..sym.
Example 34 ##STR00085## 747.83 748 (M + 1).sup..sym. Example 35
##STR00086## 743.87 744 (M + 1).sup..sym. Example 36 ##STR00087##
783.93 784 (M + 1).sup..sym. Example 37 ##STR00088## 743.87 744 (M
+ 1).sup..sym. Example 38 ##STR00089## 783.81 784 (M + 1).sup..sym.
Example 39 ##STR00090## 779.85 780 (M + 1).sup..sym. Example 40
##STR00091## 758.88 759 (M + 1).sup..sym. Example 41 ##STR00092##
730.83 731 (M + 1).sup..sym. Example 42 ##STR00093## 770.9 771 (M +
1).sup..sym. Example 43 ##STR00094## 784.92 785 (M + 1).sup..sym.
Example 44 ##STR00095## 786.94 809 (M + 1).sup..sym. Example 45
##STR00096## 800.92 801 (M + 1).sup..sym. Example 46 ##STR00097##
765.82 766 (M + 1).sup..sym. Example 47 ##STR00098## 765.82 766 (M
+ 1).sup..sym. Example 48 ##STR00099## 769.91 770 (M + 1).sup..sym.
Example 49 ##STR00100## 784.92 785 (M + 1).sup..sym. Example 50
##STR00101## 812.86 813 (M + 1).sup..sym. Example 51 ##STR00102##
768.88 769 (M + 1).sup..sym. Example 52 ##STR00103## 784.92 785 (M
+ 1).sup..sym. Example 53 ##STR00104## 794.87 795 (M +
1).sup..sym.
Example 54:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00105##
[0828] Step 1: Preparation of methyl
6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-naphthoate
(50)
[0829] A mixture of methyl 6-bromo-2-naphthoate (1.00 g, 3.77
mmol), bis(pinacolato) diboron (1.15 g, 4.53 mmol), X-Phos G2 (60
mg, 0.07 mmol) and KOAc (1.11 g, 11.3 mmol) was degassed with
nitrogen (repeat 3 times) and then dioxane (10 mL) was added and
the reaction mixture was heated to 80.degree. C. After 1 hour, the
mixture was loaded directly onto a RediSep cartridge (80 g, silica
gel) and eluted with a 0-30% EtOAc in hexane gradient. The desired
fractions were concentrated under reduced pressure to provide the
title compound as a beige solid.
Step 2: Preparation of methyl 6-(oxetan-3-yloxy)-2-naphthoate
(51)
[0830] A mixture of compound 50 (100 mg, 0.32 mmol),
copper(II)acetate hydrate (128 mg, 0.64 mmol) and Na.sub.2CO.sub.3
(135 mg, 1.28 mmol) was suspended in oxetan-3-ol (1 mL) and the
reaction mixture was stirred at 105.degree. C. After 30 minutes,
the mixture was loaded directly onto a C18 pre-cartridge and
purified through a reversed phase C18 RediSep cartridge (40 g)
eluting with a 0-70% ACN in water gradient containing 0.1% formic
acid. The desired fractions were concentrated under reduced
pressure to provide the title compound.
Step 3: Preparation of Lithium 6-(oxetan-3-yloxy)-2-naphthoate
(52)
[0831] To compound 51 (42 mg, 0.16 mmol) was added 0.33 M LiOH in
THF/MeOH/H.sub.2O (1:1:1) (0.96 mL, 0.32 mmol) and the solution was
stirred at 23.degree. C. After 2 hours, the mixture was
concentrated under reduced pressure to provide the title
compound.
Step 4: Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(oxetan-3-yloxy)-2-naphthamido)propanoyl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
[0832] The title compound was prepared in a similar manner to
Example 3 using compound 52. MS (ESI+): 774 (M+1).sup..sym.
Example 55:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan--
2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00106##
[0833] Step 1: Preparation of
(6-(methoxycarbonyl)naphthalen-2-yl)boronic Acid (53)
[0834] To compound 50 (300 mg, 0.96 mmol) and isobutyl boronic acid
(490 mg, 4.81 mmol) in MeOH/THF (1:1, 10 mL) was added 1 M aq. HCl
(3.84 mL, 3.84 mmol) and the reaction mixture was stirred at
23.degree. C. After 18 hours, the resulting layers were partitioned
and the hexanes layer was extracted further with MeOH (2.times.20
mL). The combined MeOH extracts were washed with hexanes
(2.times.20 mL) and concentrated under reduced pressure to provide
the title compound as a white solid.
Step 2: Preparation of Isopropyl 6-(oxetan-3-yl)-2-naphthoate
(54)
[0835] To a mixture of compound 53 (147 mg, 0.64 mmol), NaHMDS (117
mg, 0.64 mmol), NiI.sub.2 (5.9 mg, 0.019 mmol) and
(1R,2R)-cyclohexane-1,2-diamine hydrochloride (2.9 mg, 0.019 mmol)
in iPrOH (1.2 mL) flushed with nitrogen was added a solution of
3-iodooxetane (59 mg, 0.32 mmol) in iPrOH. This mixture was sealed,
stirred and heated in a microwave reactor (Biotage) to 80.degree.
C. for 20 minutes. After this time, the resulting mixture was
loaded directly on a pre-cartridge and purified by column
chromatography using a RediSep Gold cartridge (24 g, silica gel)
eluting with a 0-40% EtOAc in hexanes gradient. The desired
fractions were concentrated under reduced pressure to provide the
title compound as the isopropyl ester
Step 3: Preparation of Lithium 6-(oxetan-3-yl)-2-naphthoate
(55)
[0836] The title compound was prepared in a similar manner to
compound 52 using compound 54.
Step 4: Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(6-(oxetan-3-yl)-2-naphthamido)propanoyl)-4-(5-(2-hydroxypropan--
2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
[0837] The title compound was prepared in a similar manner to
Example 3 using compound 55. MS (ESI+): 758 (M+1).sup..sym.
Example 56:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(-
5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00107##
[0838] Step 1: Preparation of
4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzoic Acid (56)
[0839] To a solution of 4-(chlorosulfonyl)benzoic acid (250 mg,
1.13 mmol) in MeOH (5 mL) was added 3,3-difluorocyclobutan-1-amine
hydrochloride (Enamine, NJ, catalog #EN300-78062) (197.0 mg, 1.356
mmol) and TEA (395 .mu.L, 2.84 mmol) and the reaction mixture was
stirred at 23.degree. C. After 18 hours, the reaction mixture was
quenched with 1 M aq. HCl (4.5 mL) and the resulting beige mixture
was filtered to provide the title compound as a beige solid.
Step 2: Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(4-(N-(3,3-difluorocyclobutyl)sulfamoyl)benzamido)propanoyl)-4-(-
5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
[0840] The title compound was prepared in a similar manner to
Example 3 using compound 56. MS (ESI+): 821 (M+1).sup..sym.
Example 57:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(3-phenylureido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3--
triazol-1-yl)pyrrolidine-2-carboxamide
##STR00108##
[0842] To a suspension of Intermediate J (50 mg, 0.085 mmol) in DCM
(1 mL) cooled to 0.degree. C. in an ice bath was added phenyl
isocyanate (10.5 .mu.L, 0.095 mmol) and iPr.sub.2EtN (44.5 .mu.L,
0.255 mmol) and this solution was allowed to stand at 0.degree. C.
After 18 hours, this solution was loaded directly onto a RediSep
cartridge (12 g, silica gel) and eluted with a 0-15% MeOH in DCM
gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound. MS (ESI+): 668
(M+1).sup..sym.
[0843] The following compounds were prepared in a similar manner as
Example 57 substituting phenyl isocyanate with a series of
commercially available isocyanates.
TABLE-US-00003 Example Structure/Name MW MS (ESI+) Example 58
##STR00109## 716.83 717 (M + 1).sup..sym. Example 59 ##STR00110##
734.77 735 (M + 1).sup..sym. Example 60 ##STR00111## 719.83 720 (M
+ 1).sup..sym. Example 61 ##STR00112## 719.2 719.5 (M +
1).sup..sym. Example 62 ##STR00113## 672.82 673 (M + 1).sup..sym.
Example 63 ##STR00114## 716.83 717 (M + 1).sup..sym. Example 64
##STR00115## 750.88 751 (M + 1).sup..sym. Example 65 ##STR00116##
680.79 681 (M + 1).sup..sym. Example 66 ##STR00117## 691.78 692 (M
+ 1).sup..sym. Example 67 ##STR00118## 744.86 745 (M +
1).sup..sym.
Example 68:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyc-
lohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00119##
[0845] To a suspension of Intermediate J (50 mg, 0.085 mmol) and
iPr.sub.2EtN (44.5 .mu.L, 0.255 mmol) in DCM (1 mL) cooled to
0.degree. C. in an ice bath was added naphthalene-2-sulfonyl
chloride (21.5 mg, 0.095 mmol) and this solution was allowed to
stand at 0.degree. C. After 18 hours, this solution was loaded
directly onto a RediSep cartridge (12 g, silica gel) and eluted
with a 0-15% MeOH in DCM gradient. The desired fractions were
concentrated under reduced pressure to provide the title compound.
MS (ESI+): 738 (M+1).sup..sym.
[0846] The following compounds were prepared in a similar manner as
Example 68 substituting naphthalene-2-sulfonyl chloride with a
series of commercially available sulfonyl chlorides.
TABLE-US-00004 Example Structure/Name MW MS (ESI+) Example 69
##STR00120## 723.79 724 (M + 1).sup..sym. Example 70 ##STR00121##
753.81 754 (M + 1).sup..sym.
Example 71:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazo-
l-1-yl)pyrrolidine-2-carboxamide
##STR00122##
[0847] Step 1: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-1-h-
ydroxy-2-oxoethyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2-
,3-triazol-1-yl)pyrrolidine-2-carboxamide (57)
[0848] To a solution of Intermediate I (152 mg, 0.276 mmol),
Intermediate C (106 mg, 0.662 mmol) and HATU (124 mg, 0.331 mmol)
in DMF (2.7 mL) was added iPr.sub.2EtN (193 .mu.L, 1.104 mmol) and
the reaction mixture was stirred at 23.degree. C. After 1 hour,
residual Intermediate I was consumed by reacting with additional
HATU (60 mg, 0.158 mmol) and benzylamine (22 .mu.L, 0.2 mmol). The
reaction mixture was loaded directly onto a C18 pre-cartridge and
purified by column chromatography using reverse phase C18 RediSep
Gold cartridge (80 g) eluting with a 0-100% ACN in water gradient
containing 0.1% formic acid. The desired fractions were
concentrated under reduced pressure to provide the title
compound.
Step 2: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)tetrahydrofuran-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazo-
l-1-yl)pyrrolidine-2-carboxamide
[0849] To a solution of compound 57 (50 mg, 0.073 mmol) in DMSO (1
mL) was added IBX (45 wt %, 90 mg, 0.145 mmol) and the reaction
mixture was stirred at 23.degree. C. After 18 hours, additional IBX
(90 mg, 0.145 mmol) was added and the mixture was stirred for 6
hours. The mixture was then quenched with 10% aq.
Na.sub.2S.sub.2O.sub.3 (1 mL) and loaded directly onto a C18
pre-cartridge and purified by column chromatography using reverse
phase C18 RediSep cartridge (15.5 g) eluting with a 0-70% ACN in
water gradient containing 0.1% formic acid. The desired fractions
were concentrated under reduced pressure to provide the title
compound as a white solid. MS (ESI+): 688 (M+1).sup..sym.
Example 72:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)py-
rrolidine-2-carboxamide
##STR00123##
[0851] The title compound was prepared in a similar manner to
Example 71 using Intermediate D. MS (ESI+): 716 (M+1).sup..sym.
Examples 73 and 74: Diastereomers of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)py-
rrolidine-2-carboxamide (Example 72)
[0852] The diasteomeric mixture of Example 72 (180 mg, 0.25 mmol)
was separated using a Semi-Prep SFC ChiralPak ID column
(10.times.250 mm, 5 .mu.m) with an isocratic 40% MeOH+10 mM
ammonium formate at 10 mL/min, 100 Bar, 35.degree. C. to provide
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N--((R or
S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2-
,3-triazol-1-yl)pyrrolidine-2-carboxamide, Example 73 (second
eluting peak) and
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N--((S or
R)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H--
1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide, Example 74 (first
eluting peak). MS (EST+): 716 (M+1) 716 (M+1).sup.
Example 75:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,-
3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00124##
[0853] Step 1: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-h-
ydroxy-2-oxoethyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (59)
[0854] To a mixture of Intermediate I (222 mg, 0.405 mmol),
Intermediate E (92.5 mg, 0.486 mmol) and HATU (154 mg, 0.405 mmol)
in DMF (2 mL) was added iPr.sub.2EtN (211 .mu.L, 1.21 mmol) and the
reaction mixture was stirred at 23.degree. C. After 1 hour, water
(10 mL) was added and the mixture extracted with EtOAc (2.times.20
mL). The combined extracts were washed with 1 M aq. HCl (10 mL) and
then sat. aq. NaHCO.sub.3 (10 mL). This extract was dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. This
residue was purified by column chromatography using a RediSep
cartridge (12 g, silica gel) eluting with a 0-10% MeOH in DCM
gradient. The desired fractions concentrated under reduced pressure
to provide the title compound.
Step 2: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,-
3-triazol-1-yl)pyrrolidine-2-carboxamide
[0855] To a solution of compound 59 (146 mg, 0.20 mmol) in DCM (8
mL) was added 10% palladium on carbon (475 mg, 0.44 mmol) and the
reaction mixture was stirred at 23.degree. C. After 30 minutes, DMP
(189 mg, 0.44 mmol) was added and the mixture was stirred at
23.degree. C. After 2 hours, the mixture was quenched with 10% aq.
Na.sub.2S.sub.2O.sub.3 (1 mL), diluted with sat. aq. NaHCO.sub.3 (2
mL) and then filtered through a plug of celite. The celite plug was
rinsed further with DCM (10 mL) and MeOH (5 mL). The combined
filtrates were partitioned using an Isolute phase separator and the
combined organic extract was concentrated under reduced pressure.
This residue was purified by column chromatography using a reverse
phase C18 RediSep Gold cartridge (12 g) eluting with a 20-100% ACN
in water gradient containing 0.1% formic acid. The desired
fractions were concentrated under reduced pressure to provide the
title compound. MS (ESI+): 718 (M+1).sup..sym.
Example 76:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00125##
[0857] To a mixture of 4-((difluoromethyl)sulfonyl)benzoic acid
(Enamine, NJ, catalog #EN300-09067) (512 mg, 2.17 mmol),
Intermediate L (1.3 g, 2.17 mmol) and HATU (824 mg, 2.17 mmol) in
DMF (10 mL) was added iPr.sub.2EtN (1.13 mL, 6.5 mmol) and the
reaction mixture was stirred at 23.degree. C. for 1 hour. The
mixture was partitioned between EtOAc (100 mL) and water (50 mL)
and the aqueous layer extracted with EtOAc (100 mL). The combined
extracts were dried over MgSO.sub.4, filtered and concentrated
under reduced pressure. This residue was purified by column
chromatography using a RediSep Gold cartridge (120 g, silica gel)
eluting with a 0-10% MeOH in DCM gradient. The desired fractions
were concentrated under reduced pressure to provide the title
compound as a white solid. MS (ESI+): 782 (M+1).sup..sym.; .sup.1H
NMR (300 MHz, CD.sub.3OD): .delta. 8.18 (2H, d, J=7.8 Hz), 8.06
(2H, d, J=7.8 Hz), 7.54 (1H, s), 6.77 (1H, t, J.sub.H-F=53 Hz),
5.94-5.80 (1H, m), 5.06-4.95 (1H, m), 4.56 (1H, t, J=8 Hz),
4.43-4.25 (2H, m), 3.10-2.64 (4H, m), 2.57-2.34 (4H, m), 2.06 (2H,
t, J=12 Hz), 1.91 (1H, d, J=12 Hz), 1.74 (5H, br s), 1.66 (6H, s),
1.52-0.90 (7H, m) ppm.
[0858] The following compounds were prepared in a similar manner as
Example 76 substituting 4-((difluoromethyl)sulfonyl)benzoic acid
with a series of commercially available carboxylic acids. The
reaction mixtures were purified, as in Example 76, by column
chromatography using a RediSep Gold silica gel cartridge eluting
with a 0-10% MeOH in DCM gradient. Alternately, the crude DMF
mixtures were purified directly by reverse phase column
chromatography using a C18 RediSep Gold cartridge eluting with a
0-60% ACN in water gradient containing 0.1% formic acid. The
desired fractions were concentrated under reduced pressure to
provide the title compounds as white solids.
TABLE-US-00005 Example Structure/Name MW MS (ESI+) Example 77
##STR00126## 745.91 746 (M + 1).sup..sym. Example 78 ##STR00127##
668.81 669 (M + 1).sup..sym. Example 79 ##STR00128## 759.94 760 (M
+ 1).sup..sym. Example 80 ##STR00129## 707.84 708 (M + 1).sup..sym.
Example 81 ##STR00130## 734.86 735 (M + 1).sup..sym. Example 82
##STR00131## 771.95 772 (M + 1).sup..sym. Example 83 ##STR00132##
786.96 787 (M + 1).sup..sym. Example 84 ##STR00133## 722.86 723 (M
+ 1).sup..sym. Example 85 ##STR00134## 722.86 723 (M + 1).sup..sym.
Example 86 ##STR00135## 722.86 723 (M + 1).sup..sym. Example 87
##STR00136## 789.96 790 (M + 1).sup..sym. Example 88 ##STR00137##
708.83 709 (M + 1).sup..sym. Example 89 ##STR00138## 710.84 711 (M
+ 1).sup..sym. Example 90 ##STR00139## 667.82 669 (M + 1).sup..sym.
Example 91 ##STR00140## 668.81 669 (M + 1).sup..sym. Example 92
##STR00141## 784.95 785 (M + 1).sup..sym. Example 93 ##STR00142##
836.97 837 (M + 1).sup..sym. Example 94 ##STR00143## 802.96 803 (M
+ 1).sup..sym. Example 95 ##STR00144## 816.99 817 (M + 1).sup..sym.
Example 96 ##STR00145## 760.92 761 (M + 1).sup..sym. Example 97
##STR00146## 774.95 775 (M + 1).sup..sym. Example 98 ##STR00147##
774.95 775 (M + 1).sup..sym. Example 99 ##STR00148## 773.96 774 (M
+ 1).sup..sym. Example 100 ##STR00149## 785.97 786 (M +
1).sup..sym. Example 101 ##STR00150## 810.93 811 (M + 1).sup..sym.
Example 102 ##STR00151## 858.04 859 (M + 1).sup..sym. Example 103
##STR00152## 764.93 765 (M + 1).sup..sym. Example 104 ##STR00153##
785.97 786 (M + 1).sup..sym. Example 105 ##STR00154## 738.9 739 (M
+ 1).sup..sym. Example 106 ##STR00155## 800.99 802 (M +
1).sup..sym. Example 107 ##STR00156## 830.03 831 (M + 1).sup..sym.
Example 108 ##STR00157## 786.96 788 (M + 1).sup..sym. Example 109
##STR00158## 800.99 802 (M + 1).sup..sym. Example 110 ##STR00159##
800.99 802 (M + 1).sup..sym. Example 111 ##STR00160## 800.99 802 (M
+ 1).sup..sym. Example 112 ##STR00161## 828.92 830 (M +
1).sup..sym. Example 113 ##STR00162## 847.08 848 (M +
1).sup..sym.
Example 114:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)propanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de
##STR00163##
[0859] Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
-cyclohexyl-2-(4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzamido)propanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de
[0860] The title compound was prepared in a similar manner to
Example 76 using 4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzoic
acid, which was prepared in a similar manner as Example 56, step 1,
using 3,3-difluoroazetidine hydrochloride. MS (ESI+): 823
(M+1).sup..sym.
[0861] The following compounds were prepared in a similar manner as
Example 114 and Example 56, step 1, substituting
3,3-difluoroazetidine hydrochloride with other commercially
available amines. The reaction mixtures were purified by column
chromatography using a RediSep Gold silica gel cartridge eluting
with a 0-12.5% MeOH in DCM gradient. Alternatively, the crude DMF
mixtures were purified directly by reverse phase column
chromatography using a C18 RediSep Gold cartridge eluting with a
0-60% ACN in water gradient containing 0.1% formic acid. The
desired fractions were concentrated under reduced pressure to
provide the title compounds as white solids.
TABLE-US-00006 Example Structure/Name MW MS (ESI+) Example 115
##STR00164## 829.00 830 (M + 1).sup..sym.
(2S,4S)-1-((R)-2-(4-(2-oxa-6-azaspiro[3.3]heptan-6-
ylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-N-(4-(2-
amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 116 ##STR00165## 845.04 846 (M
+ 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-
thiopyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N-(3,3-
dimethyl-2-oxobutyl)sulfamoyl)benzamido)propanoyl)-
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1
yl)pyrrolidine-2-carboxamide
Example 117:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(pyrrolidin-1-ylsulfonyl)benzamido)propanoyl)-
-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxami-
de
##STR00166##
[0863] To a mixture of Intermediate M (189.3 mg, 0.3 mmol),
4-(pyrrolidin-1-ylsulfonyl)benzoic acid (77 mg, 0.31 mmol) and HATU
(141 mg, 0.37 mmol) in DMF (2 mL) was added iPr.sub.2EtN (216
.mu.L, 1.24 mmol) and the reaction mixture was stirred at
23.degree. C. After 1 hour, the mixture was directly purified by
reverse phase chromatography using a C18 RediSep Gold cartridge (50
g) and eluting with a 0-60% ACN in water gradient containing 0.1%
formic acid. The desired fractions were concentrated under reduced
pressure to provide the title compound. MS (ESI+): 833
(M+1).sup..sym.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.05
(2H, d, J=7.1 Hz), 7.90 (2H, d, J=8.0 Hz), 7.55 (1H, s), 5.90-5.88
(1H, m), 4.86-4.81 (1H, m), 4.57-4.55 (1H, m), 4.31-4.29 (2H, m),
3.50-3.41 (4H, m), 3.06-2.93 (2H, m), 2.90-2.65 (4H, m), 2.63-2.42
(2H, m), 2.00-1.85 (1H, m), 1.85 (9H, br s), 1.68-1.57 (9H, m),
1.54-1.35 (1H, m), 1.35-1.14 (3H, m), 1.13-0.84 (2H, m) ppm.
[0864] The following compounds were prepared in a similar manner as
Example 117 substituting 4-(pyrrolidin-1-ylsulfonyl)benzoic acid
with other commercially available carboxylic acids. Purification
may alternatively be accomplished using normal phase chromatography
using a RediSep Gold silica gel cartridge eluting with a 0-12.5%
MeOH in DCM gradient.
TABLE-US-00007 Example Structure/Name MW MS (ESI+) Example 118
##STR00167## 749.88 750 (M + 1).sup..sym.
(2S,4S)-1-((R)-2-(2-naphthamido)-3-
cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 119 ##STR00168## 777.91 778 (M
+ 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-
(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 120 ##STR00169## 813.89 814 (M
+ 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-
((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 121 ##STR00170## 750.86 751 (M
+ 1).sup..sym. N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-
yl)quinoline-3-carboxamide Example 122 ##STR00171## 739.84 740 (M +
1).sup..sym. N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-
1H-indazole-7-carboxamide Example 123 ##STR00172## 724.83 726 (M +
1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-
cyanobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-
2-carboxamide Example 124 ##STR00173## 739.84 740 (M + 1).sup..sym.
N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-
1H-indazole-6-carboxamide Example 125 ##STR00174## 742.84 743 (M +
1).sup..sym.
N.sup.1-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2- yl)terephthalamide
Example 126 ##STR00175## 744.82 745 (M + 1).sup..sym.
(2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
cyclohexyl-2-(4-nitrobenzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-
2-carboxamide Example 127 ##STR00176## 778.71 780 (M + 1).sup..sym.
(2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-
bromobenzamido)-3-cyclohexylpropanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 128 ##STR00177## 770.24 770,
772 (M + 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-
chloro-2,5-difluorobenzamido)-3-cyclohexylpropanoyl)-
4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 129 ##STR00178## 768.71 768,
770 (M + 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
cyclohexyl-2-(3,4-dichlorobenzamido)propanoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 130 ##STR00179## 716.8 717 (M
+ 1).sup..sym. N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-
6-hydroxynicotinamide Example 131 ##STR00180## 766.86 767 (M +
1).sup..sym. N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-1-
hydroxyisoquinoline-3-carboxamide Example 132 ##STR00181## 768.85
769 (M + 1).sup..sym.
N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-7-
fluoroquinoline-3-carboxamide Example 133 ##STR00182## 785.31 786
(M + 1).sup..sym.
N-((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)carbamoyl)-4-(5-
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-
7-chloroquinoline-3-carboxamide Example 134 ##STR00183## 818.96 819
(M + 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N-
cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-
2-carboxamide Example 135 ##STR00184## 832.99 833 (M + 1).sup..sym.
(2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-
cyclobutylsulfamoyl)benzamido)-3-
cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-
1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Example 136
##STR00185## 873.05 874 (M + 1).sup..sym.
(2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
cyclohexyl-2-(4-(N-(spiro[3.3]heptan-2-
yl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 137 ##STR00186## 842.93 843 (M
+ 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
cyclohexyl-2-(4-(N-(2,2-
difluoroethyl)sulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 138 ##STR00187## 847.01 848 (M
+ 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
cyclohexyl-2-(4-(piperidin-1-
ylsulfonyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 139 ##STR00188## 835 836 (M +
1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(N-
(tert-butyl)sulfamoyl)benzamido)-3-
cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-
1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide Example 140
##STR00189## 854.99 855 (M + 1).sup..sym.
(2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N-
phenylsulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 141 ##STR00190## 832.99 833 (M
+ 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
cyclohexyl-2-(4-(N-cyclopropyl-N-
methylsulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 142 ##STR00191## 847.01 847.9
(M + 1).sup..sym. (2S,4S)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3-
cyclohexyl-2-(4-(N-cyclopropyl-N-
ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 143 ##STR00192## 847.01 847.9
(M + 1).sup..sym. (2S,4R)-N-(4-(2-amino-2-oxoacetyl)-1,1-
dioxidotetrahydro-2H-thiopyran-4-yl)-1-((R)-3- cyclohexyl-2-(4-(N-
cyclopentylsulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide
Example 144:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamido)propano-
yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbox-
amide
##STR00193##
[0865] Step 1: Preparation of
4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzoic Acid (60)
[0866] The title compound was prepared in a similar manner as in
compound 56 using dicyclopropylamine hydrochloride (Enamine, NJ,
catalog #EN300-154277).
Step 2: Preparation of
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dicyclopropylsulfamoyl)benzamido)propano-
yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbox-
amide
[0867] The title compound was prepared in a similar manner to
Example 117 using 4-((3,3-difluoroazetidin-1-yl)sulfonyl)benzoic
acid and Intermediate M. MS (ESI+): 860 (M+1).sup..sym.
Example 145:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(naphthalene-2-sulfonamido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00194##
[0869] The title compound was prepared in a similar manner as
Example 68 using Intermediate M. MS (ESI+): 786 (M+1).sup..sym.
Example 146:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-4--
yl)-1-((R)-3-cyclohexyl-2-(3-(naphthalen-2-yl)ureido)propanoyl)-4-(5-(2-hy-
droxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00195##
[0871] The title compound was prepared in a similar manner as
Example 57 using Intermediate M. MS (ESI+): 765 (M+1).sup..sym.
Example 147:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)-4-(5-(2-hydroxypropan-2-yl)-
-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00196##
[0873] To a solution of compound 59 (82 mg, 0.11 mmol) in DCM (4.4
mL) at 23.degree. C. was added DMP (106 mg, 0.25 mmol) and the
reaction mixture was stirred at 23.degree. C. for 18 hours. After
this time, the reaction was quenched with 10% aq.
Na.sub.2S.sub.2O.sub.3 (500 .mu.L) and the resulting mixture was
loaded directly onto a C18 pre-cartridge and purified using a C18
RediSep Gold cartridge (24 g) eluting with a 10-60% ACN in water
gradient containing 0.1% formic acid. The desired fractions were
concentrated under reduced pressure to provide the title compound
as a white solid. MS (ESI+): 735 (M+1).sup..sym.
Example 148:
(2S,4S)--N-(4-(2-amino-2-oxoacetyl)-1-oxidotetrahydro-2H-thiopyran-4-yl)--
1-((R)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4--
(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00197##
[0875] To a solution of Example 76 (100 mg, 0.128 mmol) in DCM (5
mL) was added mCPBA (70 wt %, 21.5 mg, 0.096 mmol) and the reaction
mixture was stirred at 23.degree. C. for 30 minutes. After this
time, the reaction was partitioned with sat. aq. NaHCO.sub.3 (5 mL)
and the organic extract was dried over MgSO.sub.4, filtered and
concentrated under reduced pressure. This residue was purified by
reverse phase chromatography using a C18 RediSep Gold cartridge (30
g) eluting with a 10-60% ACN in water gradient containing 0.1%
formic acid. The desired fractions were concentrated under reduced
pressure to provide the title compound as a white solid. MS (ESI+):
798 (M+1).sup..sym.
Example 149:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)tetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-tri-
azol-1-yl)pyrrolidine-2-carboxamide
##STR00198##
[0877] The title compound was prepared in a similar manner as
Example 75 using Intermediate F. MS (ESI+): 704 (M+1).sup..sym.
Example 150:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1-oxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1-
,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00199##
[0879] The title compound was prepared in a similar manner as
Example 147 using compound 61. MS (ESI+): 720 (M+1).sup..sym.
Example 151:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00200##
[0880] Step 1: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-1-h-
ydroxy-2-oxoethyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxyprop-
an-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (62)
[0881] To a solution of compound 61 (50 mg, 0.07 mmol) in DCM (0.5
mL) was added mCPBA (77 wt %, 39 mg, 0.17 mmol) and the reaction
mixture was stirred at 23.degree. C. After 1 hour, the mixture was
quenched with 10% aq. Na.sub.2S.sub.2O.sub.3 (1 mL) and extracted
with DCM (2 mL). The organic extracts were concentrated under
reduced pressure. The residue was purified by column chromatography
using a RediSep cartridge (4 g, silica gel) eluting with a 0-12%
MeOH in DCM gradient. The desired fractions were concentrated under
reduced pressure to provide the title compound.
Step 2: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydrothiophen-3-yl)-4-(5-(2-hydroxypropan-2-yl)--
1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
[0882] The title compound was prepared in a similar manner as step
2 of Example 2 using compound 62, with stirring at 0.degree. C. for
18 h to obtain the title compound as a white solid. MS (ESI+): 736
(M+1).sup..sym.
Example 152:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-
-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00201##
[0883] Step 1: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-1-h-
ydroxy-2-oxoethyl)tetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-yl-
)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide (63)
[0884] The title compound was prepared in a similar manner to
Example 75 using Intermediate G.
Steps 2 and 3: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(3-(2-amino-2-o-
xoacetyl)-1,1-dioxidotetrahydro-2H-thiopyran-3-yl)-4-(5-(2-hydroxypropan-2-
-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
[0885] The title compound was prepared in a similar manner to
Example 151 using compound 63. MS (ESI+): 750 (M+1).sup..sym.
Example 153: (2S,4S)--N--((R or
S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-3-cyclohexyl-2-(4-((difluor-
omethyl)sulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-
-triazol-1-yl)pyrrolidine-2-carboxamide
##STR00202## ##STR00203##
[0886] Step 1: Preparation of tert-butyl
((2R)-1-((2S,4S)-2-((4-(2-amino-1-hydroxy-2-oxoethyl)oxepan-4-yl)carbamoy-
l)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cy-
clohexyl-1-oxopropan-2-yl)carbamate (65)
[0887] The title compound was prepared in a similar manner to
compound 38 using Intermediate D and DMF as solvent for 1 hour to
provide the title compound.
Step 2: Preparation of tert-butyl
((2R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)oxepan-4-yl)carbamoyl)-4-(5-(-
2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl--
1-oxopropan-2-yl)carbamate (66)
[0888] To a solution of compound 65 (1.72 g, 2.59 mmol) in DMSO (10
mL) was added IBX (45 wt %, 4.84 g, 7.77 mmol) and the reaction
mixture was stirred at 23.degree. C. After 18 hours, the reaction
was cooled to 0.degree. C. in an ice bath and then quenched with
10% aq. Na.sub.2S.sub.2O.sub.3 (20 mL) and extracted with EtOAc
(2.times.50 mL). The combined extracts were washed with sat. aq.
NaHCO.sub.3 (50 mL) and brine (50 mL) and then dried over
MgSO.sub.4, filtered and concentrated under reduced pressure. This
residue was purified by column chromatography using a RediSep Gold
cartridge (120 g, silica gel) eluting with a 0-25% MeOH in DCM
gradient. The desired fractions were concentrated under reduced
pressure to provide the title compound as a white solid.
Step 3: Separation of Diastereomers to Provide tert-butyl
((R)-1-((2S,4S)-2-(((R or
S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)c-
arbamate, Compound 67 (First Eluting Peak) and tert-butyl
((R)-1-((2S,4S)-2-(((R or
S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)carbamoyl)-4-(5-(2-hydroxypropan-2--
yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)c-
arbamate, Compounds, Compound 68 (Second Eluting Peak)
[0889] The mixture of diastereomers was separated in a similar
manner to Example 73 and Example 74 to provide the title
compounds.
Step 4: Preparation of (2S,4S)--N--((R or
S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R)-2-amino-3-cyclohexylpropano-
yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carbox-
amide Hydrochloride (69)
[0890] The title compound was prepared in a similar manner to last
step of Intermediate J using compound 67.
Steps 5: Preparation of (2S,4S)--N--((R or
S)-4-(2-amino-2-oxoacetyl)oxepan-4-yl)-1-((R or
S)-3-cyclohexyl-2-(4-((difluoromethyl)sulfonyl)benzamido)propanoyl)-4-(5--
(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide
[0891] The title compound was prepared in a similar manner to
Example 3 using compound 69 with a 1 hour reaction time. MS (ESI+):
780 (M+1).sup..sym.
[0892] The following compounds were prepared in a similar manner as
Example 153 substituting 4-((difluoromethyl)sulfonyl)benzoic acid
with other commercially available carboxylic acids.
TABLE-US-00008 Example Structure/Name MW MS (ESI+) Example 154
##STR00204## 769.91 770 (M + 1).sup..sym. (2S,4S)-N-((R or
S)-4-(2-amino-2-oxoacetyl)oxepan-4- yl)-1-((R)-3-cyclohexyl-2-(4-
(cyclopropylsulfonyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide Example 155 ##STR00205## 784.92 785 (M
+ 1).sup..sym. (2S,4S)-N-((R or S)-4-(2-amino-2-oxoacetyl)oxepan-4-
yl)-1-((R)-3-cyclohexyl-2-(4-(N-
cyclopropylsulfamoyl)benzamido)propanoyl)-4-(5-(2-
hydroxypropan-2-yl)-1H-1,2,3-triazol-1-
yl)pyrrolidine-2-carboxamide
Example 156:
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide
##STR00206## ##STR00207##
[0893] Step 1: Preparation of methyl
(2S,4R)-1-((R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoyl)-4-hy-
droxypyrrolidine-2-carboxylate (70)
[0894] To a suspension of
(R)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid
(Chem-Impex, IL, catalog/t 03553) (10.0 g, 36.9 mmol) and HATU
(15.4 g, 40.6 mmol) in DCM (100 mL) was added methyl
(2S,4R)-4-hydroxypyrrolidine-2-carboxylate (CombiBlocks, CA,
catalog #OR-0651) (7.38 g, 40.6 mmol) and iPr.sub.2EtN (9.7 mL,
55.4 mmol) and the reaction mixture was stirred at 23.degree. C.
After 18 hours, the reaction was quenched with water (100 mL) and
sat. aq. NaHCO.sub.3 (100 mL) and extracted with DCM (3.times.75
mL). The combined extracts were concentrated under reduced
pressure. This residue was purified by column chromatography using
RediSep cartridge (120 g, silica gel) eluting with a 20-100% EtOAc
in hexanes gradient. The desired fractions were concentrated under
reduced pressure to provide the title compound.
Step: 2: Preparation of methyl
(2S,4R)-1-((R)-2-amino-3-cyclohexylpropanoyl)-4-hydroxypyrrolidine-2-carb-
oxylate (71)
[0895] To a solution of compound 70 (10.6 g, 26.6 mmol) in MeOH
(100 mL) was added 36% aq. HCl (3.0 mL) and heated to 50.degree. C.
After 18 hours, the mixture was concentrated under reduced
pressure. The residual solvent was removed by azeotrope with
toluene (3.times.20 mL) to provide the title compound.
Step 3: Preparation of methyl
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-hydroxypyrrolid-
ine-2-carboxylate (72)
[0896] To a yellow solution of compound 71 (26.6 mmol) and
iPr.sub.2EtN (9.3 mL, 53.2 mmol) in DCM (100 mL) was added pyridine
(105 .mu.L, 1.3 mmol) and 2-naphthoyl chloride (5.58 g, 29.3 mmol)
and the reaction mixture was stirred at 23.degree. C. After 2 h
time, the reaction was quenched with water (100 mL) and extracted
with DCM (3.times.75 mL). The combined extracts were washed with
brine and concentrated under reduced pressure. The resulting brown
solid was dissolved in DCM (50 mL) and cooled to 0.degree. C. This
solution was treated with hexanes (50 mL) added slowly to help
induce crystallization. The suspension was cooled to -20.degree. C.
for 1 hour and then filtered and the solid was washed with hexanes
(2.times.15 mL) to provide the title compound as a white solid.
Step 4: Preparation of
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-hydroxypyrrolid-
ine-2-carboxylic Acid (73)
[0897] The title compound was prepared in a similar manner to
Intermediate I, Step 8, using compound 72 and stirring at room
temperature for 3 h.
Steps 5-6: Preparation of
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide
[0898] The title compound was prepared in a similar manner to
Example 71 using compound 73 and Intermediate B. MS (ESI+): 593
(M+1) In step 6, the reaction mixture was stirred for 18 hours at
room temperature.
Example 157:
(S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoac-
etyl)tetrahydro-2H-pyran-4-yl)-4-oxopyrrolidine-2-carboxamide
##STR00208##
[0900] The title compound was prepared in a similar manner as step
2 of Example 2 using
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-1-h-
ydroxy-2-oxoethyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxa-
mide and run at 23.degree. C. for 18 hours. MS (ESI+): 591
(M+1).sup..sym.
Example 158:
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-
-yl)pyrrolidine-2-carboxamide
##STR00209##
[0902] To a suspension of
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-o-
xoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide
(Example 156) (100 mg, 0.169 mmol), uracil (TCI, catalog #U0013)
(44 mg, 0.389 mmol) and triphenylphosphine (102 mg, 0.389 mmol) in
THF (1 mL) was added DIAD (76 .mu.L, 0.389 mmol) and the reaction
mixture was stirred at 23.degree. C. After 1 hour, the mixture was
loaded onto a C18 precartridge (5 g) and dried under vacuum. This
material was purified by reverse phase chromatography using a C18
reverse phase RediSep cartridge (30 g) eluting with a 15-80% ACN in
water gradient containing 0.1% formic acid. The desired fractions
were concentrated under reduced pressure to provide the title
compound as a white solid. MS (ESI+): 709 (M+Na).sup..sym.
[0903] The following compounds were prepared in a similar manner as
Example 158 substituting uracil with other commercially available
heterocyclic/heteroaromatic compounds.
TABLE-US-00009 Example Structure/Name MW MS (ESI+) Example 159
##STR00210## 670.75 671 (M + 1).sup..sym.
(2S,4S)-1-((R)-2-(2-naphthamido)-3-
cyclohexylpropanoyl)-N-(4-(2-amino-2-
oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(6-
oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide Example 160
##STR00211## 709.79 710 (M + 1).sup..sym.
(2S,4S)-1-((R)-2-(2-naphthamido)-3-
cyclohexylpropanoyl)-N-(4-(2-amino-2-
oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-oxo-
[1,2,4]triazolo[4,3-.alpha.]pyridin-2(3H)-
yl)pyrrolidine-2-carboxamide Example 161 ##STR00212## 721.8 744 (M
+ Na).sup..sym. (2S,4S)-1-((R)-2-(2-naphthamido)-3-
cyclohexylpropanoyl)-N-(4-(2-amino-2-
oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(1,3-
dioxoisoindolin-2-yl)pyrrolidine-2-carboxamide Example 162
##STR00213## 673.76 674 (M + 1).sup..sym.
(2S,4S)-1-((R)-2-(2-naphthamido)-3-
cyclohexylpropanoyl)-N-(4-(2-amino-2-
oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-((5-
methylisoxazol-3-yl)oxy)pyrrolidine-2-carboxamide Example 163
##STR00214## 705.2 727 (M + Na).sup..sym.
(2S,4S)-1-((R)-2-(2-naphthamido)-3-
cyclohexylpropanoyl)-N-(4-(2-amino-2-
oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(3-chloro-6-
oxopyridazin-1(6H)-yl)pyrrolidine-2-carboxamide Example 164
##STR00215## 669.77 670 (M + 1).sup..sym.
(2S,4S)-1-((R)-2-(2-naphthamido)-3-
cyclohexylpropanoyl)-N-(4-(2-amino-2-
oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-(2-oxopyridin-
1(2H)-yl)pyrrolidine-2-carboxamide
Example 165:
(4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro--
2H-pyran-4-yl)boronic Acid
##STR00216##
[0904] Step 1: Preparation of
2-methyl-N-(tetrahydro-4H-pyran-4-ylidene)propane-2-sulfinamide
(75)
[0905] Into a 100 mL round-bottom flask equipped with a magnetic
stir bar and under nitrogen was added tetrahydropyran-4-one
(Combi-Block, CA, catalog #AM-1010) (1.84 g, 18.4 mmol),
2-methyl-2-propanesulfinamide (2.25 g, 18.4 mmol), Ti(OiPr).sub.4
(8.1 mL, 37.0 mmol) and THF (anhydrous, 25 mL). The orange solution
was refluxed for 2 hours. TLC (EtOAc:hexanes 1:1) analysis revealed
completion of reaction. The mixture was cooled to 23.degree. C. and
quenched with sat. aq. NaHCO.sub.3 (4 mL) and filtered through a
pad of celite. The resulting yellow filtrate was concentrated under
reduced pressure. The residue was purified by column chromatography
using a RediSep cartridge (50 g, silica gel) eluting with
hexane:EtOAc (1:1). The desired fractions were concentrated under
reduced pressure to provide the title product as a yellow oil.
Step 2: Preparation of
2-methyl-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H--
pyran-4-yl)propane-2-sulfinamide (76)
[0906] Into a 8 mL vial equipped with a magnetic stir bar and under
nitrogen was added PCy.sub.3.BF.sub.4 (11 mg, 0.03 mmol), toluene
(1.5 mL), water (300 .mu.L) and CuSO.sub.4 (5 mg, 0.03 mmol). The
blue solution was treated with benzylamine (8 .mu.L, 0.08 mmol) and
the reaction mixture was stirred at 23.degree. C. for 10 min. The
mixture was treated with compound 75 (300 mg, 1.5 mmol) as a
solution in toluene (1.0 mL), and bis(pinacolate)diboron (762 mg,
3.0 mmol). The resulting light brown solution was stirred at room
temperature for 24 hours. LC-MS analysis revealed product
formation. The reaction mixture was filtered through a plug of
Fluorosil (5 cm.times.3 cm), eluting with EtOAc (3.times.15 mL).
The filtrate was concentrated under reduced pressure to provide the
title compound as an oil.
Step 3: Preparation of
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)tetrahydro-2H-pyran-4-amin-
e Hydrochloride (77)
[0907] Into a 100 mL round-bottom flask equipped with a magnetic
stir bar and under nitrogen was added compound 76 (1.5 mmol),
methanol (1 mL) and dioxane (3 mL). The yellow solution was treated
with 4 M HCl in dioxane (3 mL, 0.75 mmol)) and stirred at
23.degree. C. for 1 hour. The reaction mixture was concentrated
under reduced pressure, resuspended in Et.sub.2O (10 mL) and the
mixture was stirred at 23.degree. C. After 20 min, the suspension
was filtered through a 0.45 .mu.M Nylon filter washing with
Et.sub.2O (2.times.2 mL) to provide the title compound as a beige
solid.
Step 4: Preparation of
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypr-
opan-2-yl)-1H-1,2,3-triazol-1-yl)-N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)tetrahydro-2H-pyran-4-yl)pyrrolidine-2-carboxamide
(78)
[0908] Into an 8 mL sample vial equipped with a magnetic stir bar
and under nitrogen was added Intermediate I (64 mg, 0.12 mmol),
compound 77 (92 mg, 0.35 mmol), PyAOP (75 mg, 0.14 mmol), DMF (1
mL) and EtN(iPr).sub.2 (61 .mu.L, 0.35 mmol). The yellow suspension
was stirred at 23.degree. C. for 18 hours. LC-MS revealed
approximately 40% product formation. The reaction was quenched with
water (5 mL) and extracted with DCM (3.times.5 mL) using a Cl-phase
separatory cartridge. The combined organics were concentrated under
reduced pressure. This residue was purified by reverse phase column
chromatography using a C18 RediSep Gold cartridge (30 g) eluting
with 5% MeOH in DCM. The desired fractions were concentrated under
reduced pressure and dried under high vacuum for 18 hours to afford
the title compound as a white solid.
Step 5: Preparation of
(4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydro-
xypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamido)tetrahydro--
2H-pyran-4-yl)boronic Acid
[0909] Into a 5 mL sample vial equipped with a magnetic stir bar
and under nitrogen was added compound 78 (14 mg, 0.019 mmol),
isobutyl boronic acid (9 mg, 0.093 mmol) in methanol (1 mL) and
hexanes (1 mL). The reaction mixture was treated with 1 M aq. HCl
(76 .mu.l, 0.076 mmol) and the biphasic suspension was stirred
rigorously at room temperature for 4 hours. The top hexanes layer
was further extracted with methanol (2.times.1 mL). The combined
methanol layers were washed with hexanes (2.times.1 mL) and
concentrated under reduced pressure to provide the title compound
as a white solid. MS (ESI+): 657.7 (M+1-18).sup..sym.
[0910] While preferred embodiments of the present disclosure have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
present disclosure. It should be understood that various
alternatives to the embodiments of the present disclosure described
herein may be employed in practicing the present disclosure. It is
intended that the following claims define the scope of the present
disclosure and that methods and structures within the scope of
these claims and their equivalents be covered thereby.
* * * * *