Heterocyclic prolinamide derivatives
This invention is directed to novel heterocyclic prolinamide derivatives of Formula (I), 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., (s) 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.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein:
W is selected from the group consisting of: —B(OH) 2 and —C(O)C(O)NR 7 R 8 ;
X is selected from the group consisting of: —O—, —S(O) p — and —N(C(O)OR 6 )—;
Y is selected from the group consisting of: —C(O)—, —SO 2 —, and —NHC(O)—;
R 1 is selected from the group consisting of:
(a) —(CH 2 ) 0-6 -aryl,
(b) —(CH 2 ) 0-6 -heteroaryl,
(c) —(CH 2 ) 0-6 —C 3-8 cycloalkyl optionally substituted with phenyl, and
(d) —(CH 2 ) 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 1-6 alkyl,
(iv) —C 0-6 alkyl-R 5 ,
(v) —C 2-6 alkenyl,
(vi) —C 2-6 alkynyl,
(vii) —C(O)R 7 ,
(viii) —CO 2 R 7 ,
(ix) —CONR 7 R 8 ,
(x) —OH,
(xi) —O—C 1-6 alkyl,
(xii) —O—C 0-6 alkyl-R 5 ,
(xiii) —SH,
(xiv) —S(O) p —C 1-6 alkyl,
(xv) —S(O) p —C 0-6 alkyl-R 5 ,
(xvi) —S(O) 2 NR 7 R 8 ,
(xvii) —NO 2 ,
(xviii) —NR 7 R 8 ,
(xix) —NHC(O)R 7 ,
(xx) —NHC(O)OR 7 ,
(xxi) —NHC(O)NR 7 R 8 ,
(xxii) —NHSO 2 C 1-6 alkyl, and
(xxiii) —NHSO 2 C 0-6 alkyl-R 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 1-4 alkyl, —COR 7 , —CO 2 R 7 , —CONR 7 R 8 , —NR 7 R 8 , —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl;
R 2 is selected from the group consisting of:
(a) —C 3-8 alkyl and
(b) —C 0-6 alkyl-R 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 1-4 alkyl,
(iii) —NR 7 R 8 ,
(iv) —OH,
(v) —O—C 1-4 alkyl,
(vi) —SH,
(vii) —S—C 1-4 alkyl;
(viii) —NR 7 SO 2 C 1-4 alkyl, and
(ix) —NR 7 C(O)OR 7 ,
R 3a is H, and R 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 10 R 11 R 12 ,
(iv) —(CH 2 ) 0-3 —NHSO 2 —C 1-4 alkyl,
(v) —(CH 2 ) 0-3 —SO 2 —C 1-4 alkyl,
(vi) —(CH 2 ) 0-3 —C(O)O—C 1-4 alkyl, and
(vii) —CN; and
wherein the heterocycle of choice (e) is additionally optionally substituted with 1 to 2 oxo groups; or
R 3a and R 3b together represent oxo;
each R 4 is independently selected from the group consisting of:
(a) —C 1-4 alkyl,
(b) -haloC 1-4 alkyl,
(c) —OH,
(d) —O—C 1-4 alkyl,
(e) —O-haloC 1-4 alkyl, and
(f) -halogen;
each R 5 is independently selected from the group consisting of:
(a) —C 3-12 cycloalkyl,
(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 1-4 alkyl,
(ii) -halogen,
(iii) —NR 7 R 8 ,
(iv) —OH,
(v) —O—C 1-4 alkyl,
(vi) —SH, and
(vii) —S—C 1-4 alkyl;
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 1-4 alkyl, —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl;
R 6 is selected from the group consisting of:
(a) —C 1-6 alkyl, and
(b) —C 0-6 alkyl-aryl;
each R 7 and each R 8 are independently selected from the group consisting of:
(a) —H,
(b) —C 1-6 alkyl,
(c) —C 0-6 alkyl-C 3-12 cycloalkyl,
(d) —C 0-6 alkyl-heterocyclyl,
(e) —C 0-6 alkyl-heteroaryl,
(f) —C 0-6 alkyl-aryl,
(g) —C 2-6 alkenyl, and
(h) —C 2-6 alkynyl,
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 1-4 alkyl,
(iii) —C(O)C 1-4 alkyl,
(iv) —OH,
(v) —OC 1-4 alkyl,
(vi) —SH,
(vii) —SC 1-4 alkyl,
(viii) —NH 2 ,
(ix) —NH(C 1-4 alkyl), and
(x) —N(C 1-4 alkyl)(C 1-4 alkyl); or
R 7 , R 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) p , and NR 9 , and wherein said heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen;
R 9 is selected from the group consisting of:
(a) —H,
(b) —C 1-4 alkyl,
(c) —C(O)—C 1-4 alkyl,
(d) —C(O)NH 2 ,
(e) —C(O)—NH(C 1-4 alkyl),
(f) —C(O)—N(C 1-4 alkyl) 2 , and
(g) —C(O)O—C 1-4 alkyl;
R 10 , R 11 , and R 12 are independently selected from the group consisting of: H, halogen, —OH and —C 1-6 alkyl; or
R 10 , R 11 and the carbon atom to which they are attached together form a C 3-12 cycloalkyl 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 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 1-6 alkyl,
(iv) —C 0-6 alkyl-R 5 ,
(v) —C 2-6 alkenyl,
(vi) —C 2-6 alkynyl,
(vii) —C(O)R 7 ,
(viii) —CO 2 R 7 ,
(ix) —CONR 7 R 8 ,
(x) —OH,
(xi) —O—C 1-6 alkyl,
(xii) —O—C 0-6 alkyl-R 5 ,
(xiii) —SH,
(xiv) —S(O) p —C 1-6 alkyl,
(xv) —S(O) p —C 0-6 alkyl-R 5 ,
(xvi) —S(O) 2 NR 7 R 8 ,
(xvii) —NO 2 ,
(xviii) —NR 7 R 8 ,
(xix) —NHC(O)R 7 ,
(xx) —NHC(O)OR 7 ,
(xxi) —NHC(O)NR 7 R 8 ,
(xxii) —NHSO 2 C 1-6 alkyl, and
(xxiii) —NHSO 2 C 0-6 alkyl-R 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 1-4 alkyl, —COR 7 , —CO 2 R 7 , —CONR 7 R 8 , —NR 7 R 8 , —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl.
3. A compound of claim 1 wherein
R 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 10 R 11 R 12 ,
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, and
(vii) —CN;
wherein the heterocycle of choice (d) is additionally optionally substituted with 1 to 2 oxo groups; or
R 3a and R 3b together represent oxo.
4. A compound of claim 1 wherein
R 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 10 R 11 R 12 ,
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, and
(vii) —CN;
wherein the heterocycle of choice (d) is additionally optionally substituted with 1 to 2 oxo groups.
5. A compound of claim 1 wherein
R 3b is selected from the group consisting of:
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 10 R 11 R 12
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, and
(vii) —CN;
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
6. A compound of claim 1 wherein
R 3b is selected from the group consisting of:
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 10 R 11 R 12 ,
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, and
(vii) —CN;
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
7. A compound of claim 1 wherein
R 2 is —C 1-6 alkyl-R 5 , wherein the alkyl group is optionally substituted with 1 to 3 substituents independently selected from:
(i) -halogen,
(ii) -haloC 1-4 alkyl,
(iii) —O—C 1-4 alkyl,
(iv) —S—C 1-4 alkyl.
8. A compound of claim 1 wherein
R 5 is —C 3-12 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(i) —C 1-4 alkyl,
(ii) -halogen,
(iii) —O—C 1-4 alkyl,
(iv) —S—C 1-4 alkyl;
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 1-4 alkyl, —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl.
9. A compound of claim 1 wherein W is —C(O)C(O)NR 7 R 8 .
10. A compound of claim 1 wherein X is —O— or —S(O) p —.
11. A compound of claim 1 having the formula (Ia):
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof wherein:
W is selected from the group consisting of: —B(OH) 2 and —C(O)C(O)NR 7 R 8 ;
X is —O— or —S(O) p ;
Y is selected from the group consisting of: —C(O)—, —SO 2 —, and —NHC(O)—;
R 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 1-6 alkyl,
(iv) —C 0-6 alkyl-R 5 ,
(v) —C 2-6 alkenyl,
(vi) —C 2-6 alkynyl,
(vii) —C(O)R 7 ,
(viii) —CO 2 R 7 ,
(ix) —CONR 7 R 8 ,
(x) —OH,
(xi) —O—C 1-6 alkyl,
(xii) —O—C 0-6 alkyl-R 5 ,
(xiii) —SH,
(xiv) —S(O) p —C 1-6 alkyl,
(xv) —S(O) p —C 0-6 alkyl-R 5 ,
(xvi) —S(O) 2 NR 7 R 8 ,
(xvii) —NO 2 ,
(xviii) —NR 7 R 8 ,
(xix) —NHC(O)R 7 ,
(xx) —NHC(O)OR 7 ,
(xxi) —NHC(O)NR 7 R 8 ,
(xxii) —NHSO 2 C 1-6 alkyl, and
(xxiii) —NHSO 2 C 0-6 alkyl-R 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 1-4 alkyl, —COR 7 , —CO 2 R 7 , —CONR 7 R 8 , —NR 7 R 8 , —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl;
R 3a is H and R 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 10 R 11 R 12 ,
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, and
(vii) —CN;
wherein the heterocycle of choice (d) is additionally optionally substituted with 1 to 2 oxo groups; or
R 3a and R 3b together represent oxo;
R 4 is selected from the group consisting of:
(a) —C 1-4 alkyl,
(b) -haloC 1-4 alkyl,
(c) —OH,
(d) —O—C 1-4 alkyl,
(e) —O-haloC 1-4 alkyl, and
(f) -halogen;
R 5 is —C 3-12 cycloalkyl optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(i) —C 1-4 alkyl,
(ii) -halogen,
(iii) —O—C 1-4 alkyl,
(iv) —S—C 1-4 alkyl;
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 1-4 alkyl, —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl;
each R 7 and each R 8 are independently selected from the group consisting of:
(a) —H,
(b) —C 1-6 alkyl,
(c) —C 0-6 alkyl-C 3-12 cycloalkyl,
(d) —C 0-6 alkyl-heterocyclyl,
(e) —C 0-6 alkyl-heteroaryl,
(f) —C 0-6 alkyl-aryl,
(g) —C 2-6 alkenyl, and
(h) —C 2-6 alkynyl,
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 1-4 alkyl,
(iii) —C(O)C 1-4 alkyl,
(iv) —OH,
(v) —OC 1-4 alkyl,
(vi) —SH,
(vii) —SC 1-4 alkyl,
(viii) —NH 2 ,
(ix) —NH(C 1-4 alkyl), and
(x) —N(C 1-4 alkyl)(C 1-4 alkyl); or
R 7 , R 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) p , and NR 9 , and wherein said heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen;
R 9 is selected from the group consisting of:
(a) —H,
(b) —C 1-4 alkyl,
(c) —C(O)—C 1-4 alkyl,
(d) —C(O)NH 2 ,
(e) —C(O)—NH(C 1-4 alkyl),
(f) —C(O)—N(C 1-4 alkyl) 2 , and
(g) —C(O)O—C 1-4 alkyl;
R 10 , R 11 , and R 12 are independently selected from the group consisting of: H, halogen, —OH and —C 1-6 alkyl; or
R 10 , R 11 and the atom to which they are attached together form a C 3-12 cycloalkyl 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 3b is selected from the group consisting of:
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 10 R 11 R 12 ,
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, and
(vii) —CN;
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
13. A compound of claim 11 wherein
R 3b is selected from the group consisting of:
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 10 R 11 R 12 ,
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, and
(vii) —CN;
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
14. A compound of claim 11 wherein W is —C(O)C(O)NH 2 .
15. A compound of claim 11 wherein Y is —C(O)—.
16. A compound of claim 11 wherein
W is —C(O)C(O)NH 2 ;
Y is —C(O)—; and
R 3b is selected from the group consisting of:
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 10 R 11 R 12 ,
(iv) —C 0-3 alkyl-NHSO 2 —C 1-4 alkyl,
(v) —C 0-3 alkyl-SO 2 —C 1-4 alkyl,
(vi) —C 0-3 alkyl-C(O)O—C 1-4 alkyl, 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):
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein W is selected from the group consisting of: —B(OH) 2 and —C(O)C(O)NR 7 R 8 ;
X is selected from the group consisting of: —O—, —S(O) p — and —N(C(O)OR 6 )—;
Y is selected from the group consisting of: —C(O)—, —SO 2 —, and —NHC(O)—;
R 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 1-6 alkyl,
(iv) —C 0-6 alkyl-R 5 ,
(v) —C 2-6 alkenyl,
(vi) —C 2-6 alkynyl,
(vii) —C(O)R 7 ,
(viii) —CO 2 R 7 ,
(ix) —CONR 7 R 8 ,
(x) —OH,
(xi) —O—C 1-6 alkyl,
(xii) —O—C 0-6 alkyl-R 5 ,
(xiii) —SH,
(xiv) —S(O) p —C 1-6 alkyl,
(xv) —S(O) p —C 0-6 alkyl-R 5 ,
(xvi) —S(O) 2 NR 7 R 8 ,
(xvii) —NO 2 ,
(xviii) —NR 7 R 8 ,
(xix) —NHC(O)R 7 ,
(xx) —NHC(O)OR 7 ,
(xxi) —NHC(O)NR 7 R 8 ,
(xxii) —NHSO 2 C 1-6 alkyl, and
(xxiii) —NHSO 2 C 0-6 alkyl-R 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 1-4 alkyl, —COR 7 , —CO 2 R 7 , —CONR 7 R 8 , —NR 7 R 8 , —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl;
R 2 is selected from the group consisting of:
(a) —C 3-8 alkyl and
(b) —C 0-6 alkyl-R 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 1-4 alkyl,
(iii) —NR 7 R 8 ,
(iv) —OH,
(v) —O—C 1-4 alkyl,
(vi) —SH,
(vii) —S—C 1-4 alkyl;
(viii) —NR 7 SO 2 C 1-4 alkyl, and
(ix) —NR 7 C(O)OR 7 ,
R 4 is selected from the group consisting of:
(a) —C 1-4 alkyl,
(b) -haloC 1-4 alkyl,
(c) —OH,
(d) —O—C 1-4 alkyl,
(e) —O-haloC 1-4 alkyl, and
(f) -halogen;
R 5 is selected from the group consisting of:
(a) —C 3-12 cycloalkyl,
(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 1-4 alkyl,
(ii) -halogen,
(iii) —NR 7 R 8 ,
(iv) —OH,
(v) —O—C 1-4 alkyl,
(vi) —SH, and
(vii) —S—C 1-4 alkyl;
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 1-4 alkyl, —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl;
R 6 is selected from the group consisting of:
(a) —C 1-6 alkyl, and
(b) —C 0-6 alkyl-aryl;
each R 7 and each R 8 are independently selected from the group consisting of:
(a) —H,
(b) —C 1-6 alkyl,
(c) —C 0-6 alkyl-C 3-12 cycloalkyl,
(d) —C 0-6 alkyl-heterocyclyl,
(e) —C 0-6 alkyl-heteroaryl,
(f) —C 0-6 alkyl-aryl,
(g) —C 2-6 alkenyl, and
(h) —C 2-6 alkynyl,
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 1-4 alkyl,
(iii) —C(O)C 1-4 alkyl,
(iv) —OH,
(v) —OC 1-4 alkyl,
(vi) —SH,
(vii) —SC 1-4 alkyl,
(viii) —NH 2 ,
(ix) —NH(C 1-4 alkyl), and
(x) —N(C 1-4 alkyl)(C 1-4 alkyl); or
R 7 , R 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) p , and NR 9 , and wherein said heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen;
R 9 is selected from the group consisting of:
(a) —H,
(b) —C 1-4 alkyl,
(c) —C(O)—C 1-4 alkyl,
(d) —C(O)NH 2 ,
(e) —C(O)—NH(C 1-4 alkyl),
(f) —C(O)—N(C 1-4 alkyl) 2 , and
(g) —C(O)O—C 1-4 alkyl;
R 10 , R 11 , and R 12 are independently selected from the group consisting of: H, halogen, —OH and —C 1-6 alkyl; or
R 10 , R 11 and the carbon atom to which they are attached together form a C 3-12 cycloalkyl 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 2 is —C 1-3 alkyl-R 5 , and
R 5 is-C 3-12 cycloalkyl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of:
(i) —C 1-4 alkyl,
(ii) -halogen,
(iii) —O—C 1-4 alkyl,
(iv) —S—C 1-4 alkyl;
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 1-4 alkyl, —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl.
19. A compound of claim 17 wherein
W is —C(O)C(O)NH 2 ;
X is —O— or —S(O) p —; and
Y is —C(O)—.
20. A compound of claim 1 wherein
R 1 is selected from the group consisting of:
(a) phenyl,
(b) naphthyl,
(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
(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:
(i) -halogen,
(ii) —CONR 7 R 8 ,
(iii) —S(O) p —C 1-6 alkyl,
(iv) —S(O) p —C 0-6 alkyl-R 5 ,
(v) —S(O) 2 NR 7 R 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 1-4 alkyl, —COR 7 , —CO 2 R 7 , —CONR 7 R 8 , —NR 7 R 8 , —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl.
21. A compound of claim 1 wherein n and m are each 1, and k is 0.
22. A compound of claim 1 having the formula (Ic):
or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof, wherein X is O or S(O) p
R 1 is selected from the group consisting of:
(a) phenyl,
(b) naphthyl,
(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
(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:
(i) -halogen,
(ii) —CONR 7 R 8 ,
(iii) —S(O) p —C 1-6 alkyl,
(iv) —S(O) p —C 0-6 alkyl-R 5 ,
(v) —S(O) 2 NR 7 R 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 1-4 alkyl, —COR 7 , —CO 2 R 7 , —CONR 7 R 8 , —NR 7 R 8 , —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl.
23. A compound of claim 22 wherein R 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 1 is phenyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of:
(i) -halogen,
(ii) —CONR 7 R 8 ,
(iii) —S(O) p —C 1-6 alkyl,
(iv) —S(O) p —C 0-6 alkyl-R 5 ,
(v) —S(O) 2 NR 7 R 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 1-4 alkyl, —COR 7 , —CO 2 R 7 , —CONR 7 R 8 , —NR 7 R 8 , —OH, —O—C 1-4 alkyl, —SH and —S—C 1-4 alkyl.
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-hydroxypropan-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-oxoacetyl)tetrahydro-2H-pyran-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-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-24 of 44 (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-cyclohexyl-2-(4-(piperidin-1-ylsulfonyl)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)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;
(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)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;
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)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-cyclohexyl-2-(4-((2-methoxyethyl)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-pyran-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-(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-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-cyclohexyl-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-cyclohexyl-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-cyclohexyl-2-(6-(difluoromethoxy)-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-cyclohexyl-2-(6-(trifluoromethoxy)-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-cyclohexyl-2-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)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-cyclohexyl-2-(4-(2-hydroxypropan-2-yl)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-cyclohexyl-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-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-carboxamide;
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)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)carbamoyl)-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)carbamoyl)-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-(benzofuran-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)carbamoyl)-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)carbamoyl)-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-cyclohexyl-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-cyclohexyl-2-(4-(3-hydroxyoxetan-3-yl)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-cyclohexyl-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-cyclohexyl-2-(4-(cyclopropylsulfonyl)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)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—((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)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)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]imidazole-2-carboxamide;
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)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-cyclohexyl-2-(3-fluoro-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-cyclohexyl-2-(3-methyl-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-cyclohexyl-2-(4-(cyclopentylsulfonyl)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-cyclohexyl-2-(4-(ethylsulfonyl)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-cyclohexyl-2-(4-((trifluoromethyl)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-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-((2,2-difluoroethyl)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-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-dimethylsulfamoyl)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-cyclohexyl-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-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-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-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-carboxamide;
(2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(4-(N,N-diethylsulfamoyl)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-cyclohexyl-2-(4-(morpholinosulfonyl)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-cyclohexyl-2-(3-((difluoromethyl)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-pyran-4-yl)-1-((R)-3-cyclohexyl-2-(2-((difluoromethyl)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-pyran-4-yl)-1-((R)-2-(4-(cyclobutylsulfonyl)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-pyran-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;
(2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-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-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;
(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;
(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-carboxamide;
(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-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-cyclohexyl-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-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-carboxamide;
(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;
(2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-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-cyclohexyl-2-(3-(4-(trifluoromethyl)phenyl)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-cyclohexyl-2-(3-(1-methyl-1H-indol-4-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)-2-(3-(3-chloro-4-fluorophenyl)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-cyclohexyl-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-cyclohexyl-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-cyclohexyl-2-(3-(4-phenyltetrahydro-2H-pyran-4-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)-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-cyclohexyl-2-(3-(4-(methylsulfonyl)phenyl)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-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)tetrahydro-2H-pyran-4-yl)-1-((R)-3-cyclohexyl-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-cyclohexyl-2-(4-(difluoromethoxy)phenylsulfonamido)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-oxoacetyl)tetrahydrofuran-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-(4-(2-amino-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—((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;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N—((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;
(2S,4S)-1-((R)-2-(2-naphthamido)-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;
(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-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-(methylsulfonyl)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-yl)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-yl)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-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-oxo-1,2-dihydroisoquinoline-3-carboxamide;
(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-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-yl)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-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-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-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-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-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-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-benzo[d][1,2,3]triazole-5-carboxamide;
N 1 —((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-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;
(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-triazol-1-yl)pyrrolidine-2-carboxamide;
N—((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-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)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-2H-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-carboxamide;
(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-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-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-methylsulfamoyl)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,N-dimethylsulfamoyl)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-ethylsulfamoyl)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-(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-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-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;
(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;
(2S,4S)—N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-thiopyran-4-yl)-1-((R)-2-(4-(cyclobutylsulfonyl)benzamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N 1 —((R)-1-((2S,4S)-2-((4-(2-amino-2-oxoacetyl)tetrahydro-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)-N 4 ,N 4 -dimethylterephthalamide;
(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;
(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)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-(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-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-(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-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-(2,2,2-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)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-((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-carboxamide;
(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;
(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-carboxamide;
(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;
(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-carboxamide;
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;
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;
(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;
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;
N 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;
(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;
(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;
(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-hydroxypropan-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-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;
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;
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;
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;
(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;
(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;
(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;
(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;
(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;
(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;
(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)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-ethylsulfamoyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(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;
(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)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-(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-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-oxoacetyl)-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-oxoacetyl)tetrahydrothiophen-3-yl)-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-(3-(2-amino-2-oxoacetyl)-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-oxoacetyl)-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-oxoacetyl)-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-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-hydroxypyrrolidine-2-carboxamide;
(S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-oxopyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(4-(2-amino-2-oxoacetyl)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-oxoacetyl)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-oxoacetyl)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-oxoacetyl)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-oxoacetyl)tetrahydro-2H-pyran-4-yl)-4-((5-methylisoxazol-3-yl)oxy)pyrrolidine-2-carboxamide;
(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;
(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; and
(4-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-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 claim 1 and a pharmaceutically acceptable carrier.
27. A method of controlling, alleviating, ameliorating, or slowing the progress of 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 or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.
28. The method of controlling, alleviating, ameliorating, or slowing the progress of a disease of the eye according to claim 27 wherein the method 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 controlling, alleviating, ameliorating, or slowing the progress of a disease of the eye according to claim 27 wherein the method is selected from controlling, alleviating, and slowing the progression of the disease, 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 claim 27 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 claim 1 or a pharmaceutically acceptable salt, solvate, solvate of the salt or prodrug thereof.