Carbocyclic prolinamide derivatives
This invention is directed to novel carbocyclic 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., 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 ;
R 1 is selected from the group consisting of:
(a) —(CH 2 ) 0-6 -aryl, and
(b) —(CH 2 ) 0-6 -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 6 ,
(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 6 ,
(xiii) —SH,
(xiv) —S(O) p —C 1-6 alkyl,
(xv) —S(O) p —C 0-6 alkyl-R 6 ,
(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 6 ,
(xxiv) —CONH(CH 2 ) 2-4 —[O(CH 2 ) 2-4 ] m OC 1-4 alkyl,
wherein each of the alkyl group of choices (iii), (iv), (xi), (xii), (xiv), (xv), (xxii), (xxiii) and (xxiv) 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 2a and R 2b are independently selected from the group consisting of:
(a) —H,
(b) —C 1-8 alkyl, and
(c) —C 0-6 alkyl-R 6 ,
wherein each of the alkyl group of choices (b) and (c) 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,
(ix) —NR 7 C(O)R 7 , and
(x) —NR 7 C(O)OR 7 ,
with the proviso that R 2a and R 2b are not both H;
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 —NHSO 2 —C 3-12 cycloalkyl,
(vi) —(CH 2 ) 0-3 —SO 2 —C 1-4 alkyl,
(vii) —(CH 2 ) 0-3 —C(O)O—R 7 , and
(viii) —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;
R 4 is selected from a group consisting of
(a) —H,
(b) —C 1-4 alkyl,
(c) -haloC 1-4 alkyl,
(d) —O—C 1-4 alkyl, and
(e) —O-haloC 1-4 alkyl;
R 5a and R 5b are independently selected from a group consisting of
(a) —H,
(b) —C 1-4 alkyl,
(c) -halogen,
(d) —OH,
(e) —O—C 1-4 alkyl,
(f) —SH, and
(g) —S—C 1-4 alkyl, or
R 5a , R 5b and the atom(s) to which they are attached together form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycle having a heteroatom selected from O and S(O) p , and wherein said cycloalkyl or heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen, —C 1-4 alkyl, —OH, —O—C 1-4 alkyl, —SH, —S—C 1-4 alkyl;
R 6 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;
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) and the alkynyl group of (h) are each optionally substituted with 1 to 3 groups independently selected from:
(i) -halogen,
(ii) —C(O)C 1-4 alkyl,
(iii) —C(O)NH 2 ,
(iv) —C(O)NH(C 1-4 alkyl),
(v) —C(O)N(C 1-4 alkyl)(C 1-4 alkyl)
(vi) —OH,
(vii) —OC 1-4 alkyl
(viii) —SH,
(ix) —S(O) p C 1-4 alkyl,
(x) —NH 2 ,
(xi) —NH(C 1-4 alkyl), and
(xii) —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 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 ,
(g) —C(O)O—C 1-4 alkyl; and
(h) —C(O)O—C 1-4 alkyl-aryl;
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;
n is 0, 1, 2, 3, 4 or 5;
m is 1-25; 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 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 6 ,
(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 6 ,
(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 6 ,
(xxiv) —CONHC 2-4 alkyl-(OC 2-4 alkylene) m OC 1-4 alkyl,
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, —CO 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 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(O)R 7 ,
(iv) —CONR 7 R 8 ,
(v) —OH,
(vi) —O—C 1-6 alkyl,
(vii) —S(O) p —C 1-6 alkyl,
(viii) —S(O) p —C 0-6 alkyl-R 6 ,
(ix) —S(O) 2 NR 7 R 8 ,
(x) —NHSO 2 C 1-6 alkyl, and
wherein each of the alkyl group of choices (vi), (vii), (viii) and (x) 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.
4. A compound of claim 1 wherein
R 2a is H, and R 2b is —C 1-6 alkyl-R 6 , where the alkyl portion of R 2b 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) —OH
(vi) —SH, and
(vii) —S—C 1-4 alkyl.
5. A compound of claim 1 wherein
R 2a is H, and R 2b is —C 1-6 alkyl-R 6 , and
R 6 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) —NR 7 R 8 ,
(iv) —OH,
(v) —O—C 1-4 alkyl,
(vi) —SH, and
(vii) —S—C 1-4 alkyl.
6. A compound of claim 1 wherein
R 3a is H, and R 3b is selected from the group consisting of:
wherein HAr is heteroaryl and Hcyl is heterocycle, wherein HAr and Hcyl are 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 —NHSO 2 —C 3-12 cycloalkyl,
(vi) —(CH 2 ) 0-3 —SO 2 —C 1-4 alkyl,
(vii) —(CH 2 ) 0-3 —C(O)O—R 7 , and
(viii) —CN; and
wherein Hcyl is additionally optionally substituted with 1 to 2 oxo groups.
7. 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 —C(O)C(O)NR 7 R 8 ,
X is selected from the group consisting of:
(a) —CR 10 R 11 R 12 ,
(b) —(CH 2 ) 0-3 —SO 2 —C 1-4 alkyl,
(c) —(CH 2 ) 0-3 —C(O)O—R 7 ,
(d) —(CH 2 ) 0-3 —NHSO 2 —C 1-4 alkyl, and
(e) —(CH 2 ) 0-3 —NHSO 2 —C 3-12 cycloalkyl;
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(O)R 7 ,
(iv) —CONR 7 R 8 ,
(v) —OH,
(vi) —O—C 1-6 alkyl,
(vii) —S(O) p —C 1-6 alkyl,
(viii) —S(O) p —C 0-6 alkyl-R 6 ,
(ix) —S(O) 2 NR 7 R 8 ,
(x) —NHSO 2 C 1-6 alkyl, and
wherein each of the alkyl group of choices (vi), (vii), (viii) and (x) 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 5a and R 5b are independently selected from a group consisting of
(a) —H,
(b) —C 1-4 alkyl,
(c) -halogen,
(d) —OH,
(e) —O—C 1-4 alkyl,
(f) —SH, and
(g) —S—C 1-4 alkyl, or
R 5a , R 5b and the atom(s) to which they are attached together form a 3- to 6-membered cycloalkyl or a 4- to 6-membered heterocycle having a heteroatom selected from O and S(O) p , and wherein said cycloalkyl or heterocycle is optionally substituted with 1 to 2 groups independently selected from halogen, —C 1-4 alkyl, —OH, —O—C 1-4 alkyl, —SH, —S—C 1-4 alkyl;
R 6 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) —NR 7 R 8 ,
(iv) —OH,
(v) —O—C 1-4 alkyl,
(vi) —SH, and
(vii) —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, and
(d) —C 0-6 alkyl-heterocyclyl,
wherein the alkyl group of choices (b)-(d) are each optionally substituted with 1 to 3 groups independently selected from:
(i) -halogen,
(ii) —C(O)C 1-4 alkyl,
(iii) —C(O)NH 2 ,
(iv) —C(O)NH(C 1-4 alkyl),
(v) —C(O)N(C 1-4 alkyl)(C 1-4 alkyl)
(vi) —S(O) p 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 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 ,
(g) —C(O)O—C 1-4 alkyl; and
(h) —C(O)O—C 1-4 alkyl-aryl;
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;
n is 0, 1, 2, 3, 4 or 5;
m is 1-25; and
p is 0, 1 or 2.
8. A compound of claim 1 wherein
W is —C(O)C(O)NH 2 .
9. A compound of claim 8 wherein
X is —CR 10 R 11 R 12 ,
R 10 and R 11 are each —C 1-4 alkyl, or
R 10 , R 11 and the atom to which they are attached together form a C 3-6 cycloalkyl or a 4- to 6-membered heterocycle, and
R 12 is —OH.
10. A compound of claim 9 wherein
R 5a and R 5b are independently selected from a group consisting of
(a) —H, and
(b) —C 1-4 alkyl, or
R 5a , R 5b and the atom(s) to which they are attached together form a 3- to 6-membered cycloalkyl.
11. A compound of claim 1 selected from the group consisting of:
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclobutyl)-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-(1-(2-amino-2-oxoacetyl)-cyclopropyl)-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-(1-(2-amino-2-oxoacetyl)-cyclopentyl)-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-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-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-(1-(2-amino-2-oxoacetyl)-cycloheptyl)-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-(1-(2-amino-2-oxoacetyl)-cyclooctyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(1-((2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-ylpyrrolidine-2-carboxamido)cyclohexyl)boronic acid;
(2S,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(piperidin-1-yl)pyrrolidine-2-carboxamide;
(2S,3R,4R)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-3-methoxypyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(5-((methylsulfonyl)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(5-(3-hydroxyoxetan-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
2-(1-((3S,5S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-5-((1-(2-amino-2-oxoacetyl)-cyclohexyl)carbamoyl)pyrrolidin-3-yl)-1H-1,2,3-triazol-5-yl)acetic acid;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(5-(cyclopropanesulfonamidomethyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)-benzamido)propanoyl)-4-(5-((methylsulfonyl)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)-benzamido)propanoyl)-4-(5-(3-hydroxyoxetan-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-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)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(4-(3-hydroxyoxetan-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)-benzamido)propanoyl)-4-(4-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)-benzamido)propanoyl)-4-(4-(3-hydroxyoxetan-3-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-1-((R)-3-cyclohexyl-2-(4-(methylsulfonyl)-benzamido)propanoyl)-4-(4-((methylsulfonyl)methyl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
N—((R)-1-((2S,4S)-2-((1-(2-amino-2-oxoacetyl)cyclohexyl)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-(1-(2-amino-2-oxoacetyl)cyclohexyl)-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-((1-(2-amino-2-oxoacetyl)cyclohexyl)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-((1-(2-amino-2-oxoacetyl)cyclohexyl)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-(1-(2-amino-2-oxoacetyl)cyclohexyl)-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-(1-(2-amino-2-oxoacetyl)cyclohexyl)-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-(1-(2-amino-2-oxoacetyl)cyclohexyl)-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;
N 2 —((R)-1-(2S,4S)-2-((1-(2-amino-2-oxoacetyl)cyclohexyl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-N 6 -(2,5,8,11-tetraoxatridecan-13-yl)naphthalene-2,6-dicarboxamide;
N 2 —((R)-1-((2S,4S)-2-((1-(2-amino-2-oxoacetyl)cyclohexyl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-cyclohexyl-1-oxopropan-2-yl)-N 6 -(tetracosaoxatriheptacontan-73-yl)naphthalene-2,6-dicarboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(1-(2-((2-amino-2-oxoethyl)-amino)-2-oxoacetyl)cyclohexyl)-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)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-(1-(2-(((methylsulfonyl)methyl)amino)-2-oxoacetyl)cyclohexyl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-(1-(2-oxo-2-((2,2,2-trifluoroethyl)amino)acetyl)cyclohexyl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-N-(1-(2-(oxetan-3-ylamino)-2-oxoacetyl)cyclohexyl)pyrrolidine-2-carboxamide;
(2S,4S)-1-(2-(2-naphthamido)-3-cyclohexyl-2-methylpropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-(2-(2-naphthamido)-3-(spiro[3.3]heptan-2-yl)propanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-(2-(2-naphthamido)-3-(bicyclo[2.2.1]heptan-1-yl)propanoyl)-N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-1-(3-cyclohexyl-2-methyl-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)-1-(2-(4-(methylsulfonyl)benzamido)-3-(spiro[3.3]heptan-2-yl)propanoyl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-1-(3-(bicyclo[2.2.1]heptan-1-yl)-2-(4-(methylsulfonyl)benzamido)propanoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
benzyl ((R)-2-(2-naphthamido)-3-((2S,4S)-2-((1-(2-amino-2-oxoacetyl)cyclohexyl)carbamoyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidin-1-yl)-3-oxopropyl)carbamate;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-(methylsulfonamido)propanoyl)-N-(1-(2-amino-2-oxoacetyl)cyclohexyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)-1-((R)-2-(2-naphthamido)-3-acetamidopropanoyl)-N-(1-(2-amino-2-oxoacetyl)-cyclohexyl)-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-(2-(2-amino-2-oxoacetyl)-spiro[3.3]heptan-2-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-(1-(2-amino-2-oxoacetyl)-4,4-dimethylcyclohexyl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide;
(2S,4S)—N-(2-(2-amino-2-oxoacetyl)spiro[3.3]heptan-2-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-(1-(2-amino-2-oxoacetyl)-4,4-dimethylcyclohexyl)-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; and
(2S,4S)-1-((R)-2-(2-naphthamido)-3-cyclohexylpropanoyl)-N-(6-(2-amino-2-oxoacetyl)-spiro [2.5]octan-6-yl)-4-(5-(2-hydroxypropan-2-yl)-1H-1,2,3-triazol-1-yl)pyrrolidine-2-carboxamide; or
a pharmaceutically acceptable salt, solvate, salt of the solvate, or prodrug thereof.
12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.