IP Library › Patent Application 18286615

Patent Application

App. No. 18/286,615

BICYCLIC HETEROAROMATIC INHIBITORS OF KLK5

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Patent No.: US None
App. No.: 18/286,615

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Abstract

Disclosed are compounds of formulae (I)-(IV), and pharmaceutically acceptable salts thereof, which are inhibitors of kallikrein-related peptidase 5 (KLK5). Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant KLK5 activity, such as Netherton Syndrome.

Claims (369)

1 . A compound of formula (I), or a pharmaceutically acceptable salt thereof:

wherein:

ring

is arylene or heteroarylene;

ring

is arylene or heteroarylene;

ring

is fused to ring

at two and only two adjacent positions;

ring is

aryl or heteroaryl;

ring

is aryl or heteroaryl;

J represents —CH 2 —, —NH—, —CH 2 CH 2 —, —C(O)—, —C≡C—, —O—, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, —CH(aryl)-, —C(alkyl) 2 -, —CH(cycloalkyl)-, or

K represents a bond, —O—, —NH—, —C(O)—, —CH 2 —, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, or —CH(cycloalkyl)-;

wherein at least one of J and K is a bond, —C(O)—, —CH 2 —, —CH 2 CH 2 —, —CH(alkyl)-, or —CH(aryl) 2 -;

L D represents —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —CH(F)—, —CD 2 -, —CH(D)-, —CH(OH)—, —CH(alkyl)-, —CH(cycloalkyl)-, —CHNH 2 —, —CH(NH(alkyl))—, —CH(NH(cycloalkyl))—, or a bond;

R A , independently for each occurrence, represents H, halo, hydroxyl, cyano, amino, alkyl, optionally substituted alkoxy, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, —C(O)OH, —C(O)NH 2 —, —C(O)N(alkyl) 2 -, —CH 2 C(O)OH, —NO 2 , —CH 2 NH(optionally substituted alkyl), —CH 2 NH(Boc), —CH 2 N(Boc)(optionally substituted alkyl), —CH 2 NH((cycloalkyl)alkyl), —CH 2 N(alkyl)(cycloalkyl), —CH 2 N(alkyl)((cycloalkyl)alkyl), —NH(optionally substituted alkyl), —NH(cycloalkyl), —NH((cycloalkyl)alkyl), —NH((heterocycloalkyl)alkyl), —N(alkyl) 2 , —N(alkyl)((cycloalkyl)alkyl, —N(alkyl)((heterocycloalkyl)alkyl, —NH(heteroarylalkyl), —CH 2 O(optionally substituted aryl), —C(O)O(alkyl), —C(O)NH(optionally substituted alkyl), —C(O)NH(cycloalkyl)alkyl), —NHC(O)((alkyl), or —CH 2 N(alkyl) 2 ;

R B , independently for each occurrence, represents H, oxo, —C(O)O(alkyl), halogen, cyano, amino, —C(O)OH, —CH 2 C(O)OH, —C(O)NH 2 , —C(O)NH(cycloalkyl), —C(O)NH(alkyl), —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)(alkyl), —S(O) 2 alkyl, alkylaminoalkyl, alkylaminocycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, (hydroxy)haloalkyl, or tosyl, or is optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, spirocycloalkyl, halocycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, spiroheterocycloalkyl, or (heterocycloalkyl)alkyl; or two geminal occurrences of R B taken together with the atom to which they are attached form an optionally substituted spirocycloalkyl or a spiroheterocycloalkyl;

R C , independently for each occurrence, represents H, halo, —OH, cyano, or amino, or is optionally substituted alkoxy, haloalkoxy, alkyl, cycloalkyl, heterocycloalkyl, or (heteroaryl)alkoxy;

R x is H or OH;

R D , independently for each occurrence, represents H, halo, hydroxyl, cyano, —NH 2 , —NH(Ac), —NH(alkyl), —N(alkyl) 2 , —NH(CO)(alkyl), —CH 2 NH 2 , —CH 2 NHC(O)(alkyl), —C(O)NH 2 , —C(O)OH, or —NHC(O)O(alkyl), or is optionally substituted alkyl, alkoxy, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, haloalkoxy, or haloalkyl;

R 1 represents H or optionally substituted alkyl; and

m, n, p, and q are each independently 0, 1, or 2.

2 . The compound of claim 1 , wherein:

ring

is arylene or heteroarylene;

ring

is arylene or heteroarylene;

ring

is fused to ring

at two and only two adjacent positions;

ring

is aryl or heteroaryl;

ring

is aryl;

J represents —CH 2 — or —C(O)—;

K represents —O—, —NH—, or a bond;

L D represents —CH 2 —, —CH(OH)—, or a bond;

R A , independently for each occurrence, represents H, optionally substituted alkoxy, or optionally substituted (heteroaryl)alkoxy;

R B , independently for each occurrence, represents H, oxo, or is optionally substituted alkyl, aryl, cycloalkyl, (cycloalkyl)alkyl, or heterocycloalkyl;

R C , independently for each occurrence, represents H, halo, —OH, or alkoxy;

R x is H or OH;

R D , independently for each occurrence, represents H, or is optionally substituted alkyl or alkoxy;

R 1 represents H; and

m, n, p, and q are each independently 0, 1, or 2.

3 . The compound of claim 1 or 2 , having the structure of formula (Ia):

4 . The compound of any one of claims 1-3 , having the structure of formula (Ia-1):

5 . The compound of claim 1 or 2 , having the structure of formula (Ib):

6 . The compound of claim 1 or 2 , having the structure of formula (Ic):

7 . The compound of claim 1 or 2 , having the structure of formula (Id):

wherein B 1 represents N or CH.

8 . The compound of claim 1 or 2 , having the structure of formula (Ic):

9 . The compound of claim 1 or 2 , having the structure of formula (If):

10 . The compound of claim 1 or 2 , having the structure of formula (Ig):

11 . The compound of claim 1 or 2 , having the structure of formula (Ih):

12 . The compound of claim 1 or 2 , having the structure of formula (Ij):

13 . The compound of claim 1 or 2 , having the structure of formula (Ik):

14 . The compound of any one of claims 1-13 , wherein ring

represents a 6-membered aryl or heteroaryl.

15 . The compound of any one of claims 1-14 , wherein:

represents

and

X C represents CH or N.

16 . The compound of any one of claims 1-15 , wherein

represents

17 . The compound of any one of claims 1-16 , wherein R C represents H.

18 . The compound of any one of claims 1-16 , wherein R C represents alkoxy (e.g., methoxy).

19 . The compound of any one of claims 1 and 3-18 , wherein J represents —CH 2 —, —NH—, —CH 2 CH 2 —, —C(O)—, —O—, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, —CH(aryl)-, —C(alkyl) 2 -, —CH(cycloalkyl)-, or

20 . The compound of any one of claims 1-19 , wherein -J-K- represents —CH 2 —O— or —C(O)—NH—.

21 . The compound of any one of claims 1-20 , wherein

represents

22 . The compound of any one of claims 1-21 , wherein

represents

23 . The compound of claim 1 , wherein ring

is bicyclic heteroaryl.

24 . The compound of claim 23 , wherein

represents

25 . The compound of claim 23 , wherein

represents

26 . The compound of any one of claims 1-25 , wherein R 1 is H.

27 . The compound of any one of claims 1-26 , wherein L D represents —CH 2 — or a bond.

28 . The compound of any one of claims 1-27 , wherein L D represents —CH 2 —.

29 . The compound of any one of claims 1-28 , wherein R D , independently for each occurrence, represents H, alkyl, or alkoxy.

30 . The compound of any one of claims 1-29 , wherein R D represents H.

31 . The compound of any one of claims 1-30 , wherein R B , independently for each occurrence, represents H, alkyl, cycloalkyl, (cycloalkyl)alkyl, or heterocycloalkyl.

32 . The compound of any one of claims 1-31 , wherein R B represents H.

33 . The compound of any one of claims 1-31 , wherein R B , independently for each occurrence, represents alkyl or cycloalkyl.

34 . The compound of any one of claims 1-33 , wherein R A , independently for each occurrence, represents H, optionally substituted alkoxy, or optionally substituted (heteroaryl)alkoxy.

35 . The compound of any one of claims 1-34 , wherein R A represents H.

36 . The compound of claim 1 , selected from the following table:

37 . A compound of formula (II), or a pharmaceutically acceptable salt thereof:

wherein:

ring

is arylene or heteroarylene;

ring

is arylene or heteroarylene;

ring

is fused to ring

at two and only two adjacent positions;

ring

is a bicyclic ring system, where the ring attached to ring

is aryl or heteroaryl;

ring

is aryl or heteroaryl;

K represents a bond, —O—, —NH—, —C(O)—, —CH 2 —, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, or —CH(cycloalkyl)-;

wherein at least one of J and K is a bond, —C(O)—, —CH 2 —, —CH 2 CH 2 —, —CH(alkyl)-, or —CH(aryl)-:

R A , independently for each occurrence, represents H, halo, hydroxyl, cyano, amino, alkyl, optionally substituted alkoxy, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, —C(O)OH, —C(O)NH 2 , —C(O)N(alkyl) 2 -, —CH 2 C(O)OH, —NO 2 , —CH 2 NH(optionally substituted alkyl), —CH 2 NH(Boc), —CH 2 N(Boc)(optionally substituted alkyl), —CH 2 NH((cycloalkyl)alkyl), —CH 2 N(alkyl)(cycloalkyl), —CH 2 N(alkyl)((cycloalkyl)alkyl), —NH(optionally substituted alkyl), —NH(cycloalkyl), —NH((cycloalkyl)alkyl), —NH((heterocycloalkyl)alkyl), —N(alkyl) 2 , —N(alkyl)((cycloalkyl)alkyl, —N(alkyl)((heterocycloalkyl)alkyl, —NH(heteroarylalkyl), —CH 2 O(optionally substituted aryl), —C(O)O(alkyl), —C(O)NH(optionally substituted alkyl), —C(O)NH((cycloalkyl)alkyl), —NHC(O)((alkyl), or —CH 2 N(alkyl) 2 ;

R C , independently for each occurrence, represents H, halo, —OH, cyano, or amino, or is optionally substituted alkoxy, haloalkoxy, alkyl, cycloalkyl, heterocycloalkyl, or (heteroaryl)alkoxy;

R 1 represents H or optionally substituted alkyl; and

m, n, p, and q are each independently 0, 1, or 2.

38 . The compound of claim 37 , wherein:

ring

is arylene or heteroarylene;

ring

is arylene or heteroarylene;

ring

is fused to ring

at two and only two adjacent positions;

ring

is a bicyclic ring system, where the ring attached to ring

is aryl or heteroaryl;

ring

is aryl;

J represents —CH 2 — or —C(O)—;

K represents —O— or —NH—;

L D represents —CH 2 — or —CH(alkyl)-;

R A , independently for each occurrence, represents H, cyano, alkyl, optionally substituted alkoxy, optionally substituted heteroaryl, optionally substituted aminoalkyl, —C(O)NH 2 , or —NH((cycloalkyl)alkyl);

R B , independently for each occurrence, represents H, oxo, alkoxyalkyl, or haloalkyl, or is optionally substituted alkyl, aryl, cycloalkyl, (cycloalkyl)alkyl, spirocycloalkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl;

R C , independently for each occurrence, represents H or halo, or is optionally substituted alkoxy or alkyl;

R D , independently for each occurrence, represents H, halo, cyano, or —C(O)OH, or is optionally substituted alkyl, cycloalkyl, alkoxy, haloalkoxy, or haloalkyl;

R 1 represents H or optionally substituted alkyl.

39 . The compound of claim 37 or 38 , having the structure of formula (IIa):

40 . The compound of any one of claims 37-39 , having the structure of formula (IIa-1):

41 . The compound of claim 37 or 38 , having the structure of formula (IIb):

42 . The compound of claim 37 or 38 , having the structure of formula (IIc):

43 . The compound of claim 37 or 38 , having the structure of formula (IId):

44 . The compound of claim 37 or 38 , having the structure of formula (IIe):

wherein B 1 represents N or CH.

45 . The compound of claim 37 or 38 , having the structure of formula (IIf):

46 . The compound of claim 37 or 38 , having the structure of formula (IIf-1):

47 . The compound of claim 37 or 38 , having the structure of formula (Ig):

48 . The compound of claim 37 or 38 , having the structure of formula (IIh):

49 . The compound of claim 37 or 38 , having the structure of formula (IIj):

50 . The compound of claim 37 or 38 , having the structure of formula (IIk):

51 . The compound of claim 37 or 38 , having the structure of formula (IIm):

52 . The compound of claim 37 or 38 , having the structure of formula (IIn):

53 . The compound of claim 37 or 38 , having the structure of formula (IIo):

wherein Y B is H or CH.

54 . The compound of any one of claims 37-53 , wherein ring

is a bicyclic ring system, where the ring attached to ring

is aryl.

55 . The compound of any one of claims 37-53 , wherein ring

is a bicyclic ring system, where the ring attached to ring

is heteroaryl.

56 . The compound of any one of claims 37-54 , wherein

represents

wherein ring

represents aryl, heteroaryl, or heterocycloalkyl.

57 . The compound of claim 56 , wherein ring

represents heteroaryl.

58 . The compound of claim 56 or 57 , wherein ring

represents a 5- or 6-membered heteroaryl containing at least one nitrogen atom.

59 . The compound of any one of claims 37-53 and 56-58 , wherein

represents

60 . The compound of any one of claims 37-53 and 55 , wherein

represents

wherein ring

represents aryl, heteroaryl, or heterocycloalkyl; and

X C1 and X C2 each independently represent CH or N.

61 . The compound of claim 60 , wherein ring

represents aryl or heteroaryl.

62 . The compound of claim 60 or 61 , wherein

represents

63 . The compound of any one of claims 37-58 and 60-61 , wherein R C represents H.

64 . The compound of any one of claims 37-58 and 60-61 , wherein R C , independently for each occurrence, represents alkoxy or alkyl.

65 . The compound of any one of claims 37 and 39-64 , wherein J represents —CH 2 —, —NH—, —CH 2 CH 2 —, —C(O)—, —O—, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, —CH(aryl)-, —C(alkyl) 2 -, —CH(cycloalkyl)-, or

66 . The compound of any one of claims 37-65 , wherein -J-K- represents —CH 2 —O— or —C(O)—NH—.

67 . The compound of any one of claims 37-66 , wherein ring

is aryl.

68 . The compound of any one of claims 37-67 , wherein

represents

69 . The compound of any one of claims 37-68 , wherein

represents

70 . The compound of claim 37 , wherein ring

is bicyclic heteroaryl.

71 . The compound of claim 70 , wherein

represents

72 . The compound of claim 70 , wherein

represents

73 . The compound of any one of claims 37-72 , wherein R 1 is H.

74 . The compound of any one of claims 37-73 , wherein L D represents —CH 2 — or —CH(alkyl)-.

75 . The compound of any one of claims 37-74 , wherein L D represents —CH 2 —.

76 . The compound of any one of claims 37-75 , wherein R D , independently for each occurrence, represents H, alkyl, or alkoxy.

77 . The compound of any one of claims 37-76 , wherein R D represents H.

78 . The compound of any one of claims 37-77 , wherein R B , independently for each occurrence, represents H, alkoxyalkyl, or haloalkyl, or is optionally substituted alkyl, aryl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, or (heterocycloalkyl)alkyl.

79 . The compound of any one of claims 37-78 , wherein R B , independently for each occurrence, represents optionally substituted alkyl, cycloalkyl, or heterocycloalkyl, e.g., heterocycloalkyl substituted with alkyl, hydroxyalkyl, alkoxyalkyl.

80 . The compound of any one of claims 37-79 , wherein R A , independently for each occurrence, represents H, cyano, alkyl, optionally substituted alkoxy, optionally substituted heteroaryl, or —NH((cycloalkyl)alkyl).

81 . The compound of any one of claims 37-80 , wherein R A represents H.

82 . The compound of claim 37 , selected from the following table:

83 . A compound of formula (III), or a pharmaceutically acceptable salt thereof:

wherein:

ring

is arylene or heteroarylene;

ring

is cycloalkylene, heterocycloalkylene, cycloalkenylene, or heterocycloalkenylene;

ring

is fused to ring

at two and only two adjacent positions;

ring

is a bicyclic ring system, where the ring attached to ring

is aryl or heteroaryl;

ring

is aryl or heteroaryl;

K represents a bond, —O—, —NH—, —C(O)—, —CH 2 —, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, or —CH(cycloalkyl)-;

wherein at least one of J and K is a bond, —C(O)—, —CH 2 —, —CH 2 CH 2 —, —CH(alkyl), or —CH(aryl) 2 -;

R A , independently for each occurrence, represents H, halo, hydroxyl, cyano, amino, alkyl, optionally substituted alkoxy, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, —C(O)OH, —C(O)NH 2 —, —C(O)N(alkyl) 2 -, —CH 2 C(O)OH, —NO 2 , —CH 2 NH(optionally substituted alkyl), —CH 2 N(Boc), —CH 2 N(Boc)(optionally substituted alkyl), —CH 2 NH((cycloalkyl)alkyl), —CH 2 N(alkyl)(cycloalkyl), —CH 2 N(alkyl)((cycloalkyl)alkyl), —NH(optionally substituted alkyl), —NH(cycloalkyl), —NH((cycloalkyl)alkyl), —NH((heterocycloalkyl)alkyl), —N(alkyl) 2 , —N(alkyl)((cycloalkyl)alkyl, —N(alkyl)((heterocycloalkyl)alkyl, —NH(heteroarylalkyl), —CH 2 O(optionally substituted aryl), —C(O)O(alkyl), —C(O)NH(optionally substituted alkyl), —C(O)NH((cycloalkyl)alkyl), —NHC(O)O(alkyl), or —CH 2 N(alkyl) 2 ;

R B , independently for each occurrence, represents H, oxo, —C(O)O(alkyl), halogen, cyano, amino, —C(O)OH, —CH 2 C(O)OH, —C(O)NH 2 , —C(O)NH(cycloalkyl), —C(O)NH(alkyl), —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)(alkyl), —S(O) 2 alkyl, alkylaminoalkyl, alkylaminocycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, (hydroxy)haloalkyl, or tosyl, or is optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, spirocycloalkyl, halocycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, spiroheterocycloalkyl, or (heterocycloalkyl)alkyl; or two adjacent occurrences of R B taken together with the intervening atoms form an aromatic ring; or two geminal occurrences of R B taken together with the atom to which they are attached form an optionally substituted spirocycloalkyl or a spiroheterocycloalkyl;

R C , independently for each occurrence, represents H, halo, —OH, cyano, or amino, or is optionally substituted alkoxy, haloalkoxy, alkyl, cycloalkyl, heterocycloalkyl, or (heteroaryl)alkoxy;

R 1 represents H or optionally substituted alkyl; and

m, n, p, and q are each independently 0, 1, or 2.

84 . The compound of claim 83 , wherein ring

is cycloalkylene or heterocycloalkylene.

85 . The compound of claim 83 or 84 , wherein:

ring

is arylene;

ring

is cycloalkylene;

ring

is fused to ring

at two and only two adjacent positions;

ring

is a bicyclic ring system, where the ring attached to ring

is aryl;

ring

is aryl;

J represents —O—;

K represents a bond;

L D represents —CH 2 —;

R A , independently for each occurrence, represents H, halo, alkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl;

R B , independently for each occurrence, represents H, or two adjacent occurrences of R B taken together with the intervening atoms form an aromatic ring; or two geminal occurrences of R B taken together with the atom to which they are attached form an optionally substituted spirocycloalkyl or a spiroheterocycloalkyl;

R C represents H;

R D represents H or optionally substituted alkyl;

R 1 represents H.

86 . The compound of any one of claims 83-85 , having the structure of formula (IIIa):

87 . The compound of any one of claims 83-86 , having the structure of formula (IIIa-1):

88 . The compound of any one of claims 83-85 , having the structure of formula (IIIb):

wherein X B represents CH or N.

89 . The compound of claim 88 , having the structure of formula (IIIb-1):

wherein X B represents CH or N.

90 . The compound of any one of claims 83-85 , having the structure of formula (IIIc):

wherein X B represents CH or N.

91 . The compound of claim 90 , having the structure of formula (IIIc-1):

wherein X B represents CH or N.

92 . The compound of any one of claims 83-85 , having the structure of formula (IIId):

93 . The compound of claim 92 , having the structure of formula (IIId-1):

94 . The compound of any one of claims 83-93 , wherein ring

is a bicyclic ring system, where the ring attached to ring

is aryl.

95 . The compound of any one of claims 83-94 , wherein

represents

wherein ring

represents heteroaryl.

96 . The compound of any one of claims 83-95 , wherein

represents

97 . The compound of any one of claims 83-96 , wherein R C represents H.

98 . The compound of any one of claims 83-84 and 86-97 , wherein J represents —CH 2 —, —NH—, —CH 2 CH 2 —, —C(O)—, —O—, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, —CH(aryl)-, —C(alkyl) 2 -, —CH(cycloalkyl)-, or

99 . The compound of any one of claims 83-98 , wherein -J-K- represents —O—.

100 . The compound of any one of claims 83-99 , wherein ring

is aryl.

101 . The compound of any one of claims 83-100 , wherein

represents

102 . The compound of any one of claims 83-101 , wherein

represents

103 . The compound of claim 83 , wherein ring

is bicyclic heteroaryl.

104 . The compound of any one of claims 83-103 , wherein R 1 is H.

105 . The compound of any one of claims 83-104 , wherein L D represents —CH 2 —.

106 . The compound of any one of claims 83-105 , wherein R D , independently for each occurrence, represents H or alkyl.

107 . The compound of any one of claims 83-106 , wherein two geminal occurrences of R B taken together with the atom to which they are attached form an optionally substituted spirocycloalkyl or a spiroheterocycloalkyl.

108 . The compound of any one of claims 83-107 , wherein two geminal occurrences of R B taken together with the atom to which they are attached form a substituted spiroheterocycloalkyl.

109 . The compound of any one of claims 83-108 , wherein R B represents H.

110 . The compound of any one of claims 83-109 , wherein R A , independently for each occurrence, represents H, halo, alkyl, aryl, heteroaryl, or cycloalkyl.

111 . The compound of any one of claims 83-110 , wherein R A represents H.

112 . The compound of claim 83 , selected from the following table:

113 . A compound of formula (IV), or a pharmaceutically acceptable salt thereof:

wherein:

ring

is arylene or heteroarylene;

ring

is arylene or heteroarylene;

ring

is fused to ring

at two and only two adjacent positions;

ring

is selected from the group consisting of

ring

is aryl or heteroaryl;

K represents a bond, —O—, —NH—, —C(O)—, —CH 2 —, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, or —CH(cycloalkyl)-;

wherein at least one of J and K is a bond, —C(O)—, —CH 2 —, —CH 2 CH 2 —, —CH(alkyl)-, or —CH(aryl) 2 -;

L D represents —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —CH(F)—, —CD 2 -, —CH(D)-, —CH(OH)—, —CH(alkyl)-, —CH(cycloalkyl)-, —CHNH 2 —, —CH(NH(alkyl))-, —CH(NH(cycloalkyl))-, or a bond;

R A , independently for each occurrence, represents H, halo, hydroxyl, cyano, amino, alkyl, optionally substituted alkoxy, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, —C(O)OH, —C(O)NH 2 —, —C(O)N(alkyl) 2 -, —CH 2 C(O)OH, —NO 2 , —CH 2 NH(optionally substituted alkyl), —CH 2 NH(Boc), —CH 2 N(Boc)(optionally substituted alkyl), —CH 2 NH((cycloalkyl)alkyl), —CH 2 N(alkyl)(cycloalkyl), —CH 2 N(alkyl)((cycloalkyl)alkyl), —NH(optionally substituted alkyl), —NH(cycloalkyl), —NH((cycloalkyl)alkyl), —NH((heterocycloalkyl)alkyl), —N(alkyl) 2 , —N(alkyl)((cycloalkyl)alkyl, —N(alkyl)((heterocycloalkyl)alkyl, —NH(heteroarylalkyl), —CHO(optionally substituted aryl), —C(O)O(alkyl), —C(O)NH(optionally substituted alkyl), —C(O)NH((cycloalkyl)alkyl), —NHC(O)O(alkyl), or —CH 2 N(alkyl) 2 ;

R 1 represents H or optionally substituted alkyl; and

m, p, and q are each independently 0, 1, or 2.

114 . The compound of claim 113 , wherein:

ring

is arylene;

ring

is heteroarylene;

ring

is fused to ring

at two and only two adjacent positions;

ring

is selected from the group consisting of

ring

is aryl;

J represents —CH 2 —;

K represents a bond or —O—;

LP represents —CH 2 —;

R A represents H;

R B , independently for each occurrence, represents H, oxo, or alkyl;

R D represents H;

R 1 represents H; and

m, p, and q are each independently 0, 1, or 2.

115 . The compound of claim 113 or 114 , having the structure of formula (IVa):

116 . The compound of any one of claim 113 or 115 , wherein J represents —CH 2 —, —NH—, —CH 2 CH 2 —, —C(O)—, —O—, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, —CH(aryl)-, —C(alkyl) 2 -, —CH(cycloalkyl)-, or

117 . The compound of any one of claims 113-116 , wherein -J-K- represents —CH 2 —O— or CH 2 —.

118 . The compound of any one of claims 113-117 , wherein

represents

119 . The compound of claim 113 , wherein ring

is bicyclic heteroaryl.

120 . The compound of claim 119 , wherein

represents

121 . The compound of claim 119 , wherein

represents

122 . The compound of any one of claims 113-121 , wherein R 1 is H.

123 . The compound of any one of claims 113-122 , wherein L D represents —CH 2 —.

124 . The compound of any one of claims 113-123 , wherein R D represents H.

125 . The compound of any one of claims 113-124 , wherein R B , independently for each occurrence, represents H, oxo, or alkyl.

126 . The compound of any one of claims 113-125 , wherein R A represents H.

127 . The compound of claim 113 , selected from the following table:

128 . A pharmaceutical composition, comprising a compound of any one of claims 1-127 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

129 . A method of treating or preventing a disease or condition characterized by aberrant kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-127 , or a pharmaceutically acceptable salt thereof.

130 . The method of claim 129 , wherein the disease or condition is characterized by aberrant kallikrein-related peptidase 5 (KLK5) activity.

131 . The method of claim 129 or 130 , wherein the disease or condition is a skin disease.

132 . The method of any one of claims 129-131 , wherein the disease or condition is Netherton Syndrome.

133 . The method of claim 131 , wherein the skin disease is eczema, atopic eczema, atopic dermatitis, ichthyosiform (scaly) erythroderma (IE), rosacea, or a skin infection.

134 . The method of claim 129 or 130 , wherein the disease or condition is selected from the group consisting of hypersensitivity of the immune system (atopy), hyper IgE syndrome, allergies (including allergies to food and airborne agents), asthma, allergic asthma, chronic inflammation, rhinitis, conjunctivitis, angioedema, cosinophilia, eosinophilic esophagitis, growth delay, failure to thrive, trichorrhexis invaginata (TI), respiratory tract infections, systemic infections, and gastrointestinal disorders.

135 . The method of claim 129 or 130 , wherein the disease or condition is cancer.

136 . The method of claim 135 , wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, bladder cancer, cervical cancer, glioblastoma multiforme, and neuroblastoma.

137 . A method of treating or preventing a disease or condition characterized by aberrant kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof; wherein the compound is selected from the group consisting of:

138 . The method of claim 137 , wherein the disease or condition is characterized by aberrant kallikrein-related peptidase 5 (KLK5) activity.

139 . The method of claim 137 or 138 , wherein the disease or condition is a skin disease.

140 . The method of any one of claims 137-139 , wherein the disease or condition is Netherton Syndrome.

141 . The method of claim 139 , wherein the skin disease is eczema, atopic eczema, atopic dermatitis, ichthyosiform (scaly) erythroderma (IE), rosacea, or a skin infection.

142 . The method of claim 137 or 138 , wherein the disease or condition is selected from the group consisting of rhinitis, conjunctivitis, angioedema, eosinophilia, eosinophilic esophagitis, growth delay, failure to thrive, trichorrhexis invaginata (TI), respiratory tract infections, systemic infections and gastrointestinal disorders.

143 . The method of claim 137 or 138 , wherein the disease or condition is selected from the group consisting of hypersensitivity of the immune system (atopy), hyper IgE syndrome, allergies (including allergies to food and airborne agents), asthma, allergic asthma, and chronic inflammation.

144 . The method of claim 137 or 138 , wherein the disease or condition is cancer.

145 . The method of claim 144 , wherein the cancer is selected from the group consisting of ovarian cancer, breast cancer, prostate cancer, bladder cancer, cervical cancer, glioblastoma multiforme, and neuroblastoma.

Assignments (2)

SECURITY INTEREST Recorded Jan 23, 2026

From: BIOCRYST PHARMACEUTICALS, INC.

To: WILMINGTON TRUST, NATIONAL ASSOCIATION

Reel/Frame 074485/0651 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 12, 2024

From: KOTIAN, PRAVIN L.; BABU, YARLAGADDA S.; ZHANG, WEIHE; LU, PENG-CHENG; DANG, ZHAO; RAMAN, KRISHNAN

To: BIOCRYST PHARMACEUTICALS, INC.

Reel/Frame 069233/0745 →