US2021147422A1PendingUtilityA1
Antimicrobials and methods of making and using same
Est. expiryJun 19, 2037(~10.9 yrs left)· nominal 20-yr term from priority
A61P 31/04C07D 487/04
49
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Claims
Abstract
The present disclosure relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, reducing the risk of, and delaying the onset of microbial infections in humans and animals. In some embodiments, the present disclosure provides a compound of Formula (I): or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula (AA):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
J is selected from
X is selected from a 5- or 6-membered heterocyclyl ring and phenyl, wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X ;
Z is selected from
R 1 is selected from H, C 1-3 alkyl, and C 2-4 alkenyl;
R 2 is selected from H and C 1-3 alkyl;
R 3 is selected from H and C 1-3 alkyl;
or R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring;
or R 1 and R 3 together with the nitrogen and sulfur atom to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring;
R 4 is selected from H and C 1-3 alkyl;
R 5 is selected from H and C 1-6 alkyl;
R 6 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 3-6 cycloalkyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , —SC(NH)NH 2 , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;
R 7 is selected from H and C 1-6 alkyl;
or R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring having one of the formulas:
wherein the ring is optionally substituted on a ring carbon atom with C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH;
or R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form a ring having one of the formulas:
wherein the ring is optionally substituted on a ring carbon atom with OH;
Q is selected from C 1-2 alkylene or —C(O)—;
R 21 is selected from H, C 1-6 alkyl optionally substituted with 1-3 halo;
R 8 is selected from H and halogen;
each R X is independently selected from halogen, C 1-6 alkyl, C 1-4 haloalkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b ;
or two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring;
each R a is independently selected from H and C 1-6 alkyl;
each R b is independently selected from C 2-6 alkenyl, OR c , N(R c ) 2 , —C(O)OR c , C 3-6 cycloalkyl, OC(NH)NH 2 , and aryl;
each R c is independently selected from H, C 1-6 alkyl, aryl, —C(O)aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 ; or
a compound of Formula (A):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
X is selected from a 5- or 6-membered heterocyclyl ring and phenyl, wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X ;
Z is selected from
R 1 is selected from H and C 1-3 alkyl;
R 2 is selected from H and C 1-3 alkyl;
R 3 is selected from H and C 1-3 alkyl;
or R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring;
R 4 is selected from H and C 1-3 alkyl;
R 5 is selected from H and C 1-6 alkyl;
R 6 is selected from H, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , —SC(NH)NH 2 , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;
R 7 is selected from H and C 1-6 alkyl;
or R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring having one of the formulas:
wherein the ring is optionally substituted on a ring carbon atom with C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH;
or R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form a ring having one of the formulas:
wherein the ring is optionally substituted on a ring carbon atom with OH;
Q is selected from C 1-2 alkylene or —C(O)—;
R 21 is selected from H, C 1-6 alkyl optionally substituted with 1-3 halo;
R 8 is selected from H and halogen;
each R X is independently selected from halogen, C 1-6 alkyl, C 1-4 haloalkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b ;
or two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring;
each R a is independently selected from H and C 1-6 alkyl;
each R b is independently selected from C 2-6 alkenyl, OR c , N(R c ) 2 , —C(O)OR c , C 3-6 cycloalkyl, and aryl;
each R c is independently selected from H, C 1-6 alkyl, aryl, —C(O)aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 ;
or a compound of Formula (I)
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
X is selected from a 5- or 6-membered heterocyclyl ring and phenyl, wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X ;
R 1 is selected from Hand C 1-3 alkyl;
R 2 is selected from Hand C 1-3 alkyl;
R 3 is selected from Hand C 1-3 alkyl;
or R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring;
R 4 is selected from Hand C 1-3 alkyl;
R 5 is selected from Hand C 1-6 alkyl;
R 6 is selected from H, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , —SC(NH)NH 2 , C 3-6 cycloalkyl, and 3-6 membered heterocyclyl;
R 7 is selected from H and C 1-6 alkyl;
or R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring having one of the formulas:
wherein the ring is optionally substituted on a ring carbon atom with C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH;
or R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form a ring having one of the formulas:
wherein the ring is optionally substituted on a ring carbon atom with OH;
R 8 is selected from H and halogen;
each R X is independently selected from halogen, C 1-6 alkyl, C 1-4 haloalkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b ;
or two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring;
each R a is independently selected from H and C 1-6 alkyl;
each R b is independently selected from C 2-6 alkenyl, OR c , N(R c ) 2 , —C(O)OR c , C 3-6 cycloalkyl, and aryl;
each R c is independently selected from H, C 1-6 alkyl, aryl, —C(O)aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 .
2 . The compound of claim 1 , wherein each of R 1 , R 2 , and R 3 is H.
3 . The compound of claim 1 , wherein two of R 1 , R 2 , and R 3 are H, and the other is C 1-3 alkyl.
4 . The compound of any one of claims 1 and 2 , wherein two of R 1 , R 2 , and R 3 are H, and the other is methyl.
5 . The compound of claim 1 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are C 1-3 alkyl.
6 . The compound of any one of claims 1 and 5 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are methyl.
7 . The compound of claim 1 , wherein R 1 is H; and R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring.
8 . The compound of claim 1 , wherein R 1 is H; and R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form an imidazoline.
9 . The compound of any one of claims 1 - 8 , wherein R 4 is H.
10 . The compound of any one of claims 1 - 8 , wherein R 4 is C 1-3 alkyl.
11 . The compound of any one of claims 1 - 10 , wherein one of R 5 and R 7 is H and the other is C 1-6 alkyl.
12 . The compound of any one of claims 1 - 11 , wherein R 5 is H and R 7 is C 1-6 alkyl.
13 . The compound of any one of claims 1 - 10 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
14 . The compound of any one of claims 1 - 10 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
wherein the ring is optionally substituted with C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH.
15 . The compound of any one of claims 1 - 10 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
16 . The compound of any one of claims 1 - 10 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
17 . The compound of any one of claims 1 - 10 , wherein R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring of formula
18 . The compound of any one of claims 1 - 10 , wherein R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring of formula
19 . The compound of any one of claims 1 - 16 , wherein R 6 is selected from H and C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR a .
20 . The compound of any one of claims 1 - 19 , wherein R 6 is H.
21 . The compound of any one of claims 1 - 19 , wherein R 6 is C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR a .
22 . The compound of any one of claims 1 - 19 and 21 , wherein R 6 is C 1-6 alkyl optionally substituted with OR a .
23 . The compound of any one of claims 1 - 19 , 21 , and 22 , wherein R a is H.
24 . The compound of any one of claims 1 - 19 , 21 , and 22 , wherein R a is C 1-6 alkyl.
25 . The compound of any one of claims 1 - 19 , 21 , and 22 , wherein R 6 is C 1-6 alkyl substituted with —SC(NH)NH 2 .
26 . The compound of any one of claims 1 - 16 , wherein R 6 is C 1-6 alkyl optionally substituted with halogen.
27 . The compound of any one of claims 1 - 16 and 26 , wherein R 6 is C 1-6 alkyl optionally substituted with fluoro.
28 . The compound of any one of claims 1 - 27 , wherein X is selected from a 5-membered heterocyclyl ring and phenyl, wherein each of the 5-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X .
29 . The compound of any one of claims 1 - 28 , wherein X is a 5-membered heterocyclyl ring optionally substituted with one or more R X .
30 . The compound of any one of claims 1 - 29 , wherein X is a pyrrolidinyl optionally substituted with one or more R X .
31 . The compound of any one of claims 1 - 30 , wherein X is a 2- or 3-pyrrolidinyl optionally substituted with one or more R X .
32 . The compound of any one of claims 1 - 28 , wherein X is phenyl optionally substituted with one or more R X .
33 . The compound of any one of claims 1 - 28 and 32 , wherein X is phenyl optionally substituted with three R X .
34 . The compound of any one of claims 1 - 33 , wherein R X is independently selected from halogen, C 1-6 alkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b .
35 . The compound of any one of claims 1 - 34 , wherein R X is independently selected from halogen and C 1-6 alkyl optionally substituted with one or more R b .
36 . The compound of any one of claims 1 - 35 , wherein R b is selected from C 2-6 alkenyl, OR c , N(R c ) 2 , and C 3-6 cycloalkyl.
37 . The compound of any one of claims 1 - 36 , wherein R b is selected from C 2-6 alkenyl, OR c , NH 2 , and cyclopropyl.
38 . The compound of any one of claims 1 - 37 , wherein R c is selected from H and C 1-6 alkyl.
39 . The compound of any one of claims 1 - 37 , wherein R b is selected from vinyl, OH, and NH 2 .
40 . The compound of any one of claims 1 - 39 , wherein two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring.
41 . A compound of Formula (IA):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
X is selected from a 5- or 6-membered heterocyclyl ring and phenyl, wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X ;
R 1 is selected from H and C 1-3 alkyl;
R 2 is selected from H and C 1-3 alkyl;
R 3 is selected from H and C 1-3 alkyl;
R 4 is selected from H and C 1-3 alkyl;
R 6 is selected from H, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , —SC(NH)NH 2 , C 3-6 cycloalkyl, or C 3-6 heterocyclyl;
each R X is independently selected from halogen, C 1-6 alkyl, C 1-4 haloalkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b ;
or two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring;
each R a is independently selected from H and C 1-6 alkyl;
each R b is independently selected from C 2-6 alkenyl, OR c , N(R c ) 2 , —C(O)OR c , C 3-6 cycloalkyl, and aryl;
each R c is independently selected from H, C 1-6 alkyl, aryl, —C(O)aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 .
42 . The compound of claim 41 , wherein each of R 1 , R 2 , and R 3 is H.
43 . The compound of claim 41 , wherein two of R 1 , R 2 , and R 3 are H, and the other is C 1-3 alkyl.
44 . The compound of any one of claims 41 and 42 , wherein two of R 1 , R 2 , and R 3 are H, and the other is methyl.
45 . The compound of claim 41 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are C 1-3 alkyl.
46 . The compound of any one of claims 41 and 45 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are methyl.
47 . The compound of claim 41 , wherein R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring.
48 . The compound of claim 41 , wherein R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form an imidazoline.
49 . The compound of any one of claims 41 - 48 , wherein R 4 is H.
50 . The compound of any one of claims 41 - 48 , wherein R 4 is C 1-3 alkyl.
51 . The compound of any one of claims 41 - 50 , wherein R 6 is selected from H and C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR.
52 . The compound of any one of claims 41 - 51 , wherein R 6 is H.
53 . The compound of any one of claims 41 - 51 , wherein R 6 is C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR a .
54 . The compound of any one of claims 41 - 51 and 53 , wherein R 6 is C 1-6 alkyl optionally substituted with OR a .
55 . The compound of any one of claims 41 - 51 , 53 , and 54 , wherein R a is H.
56 . The compound of any one of claims 41 - 51 , 53 , and 54 , wherein R a is C 1-6 alkyl.
57 . The compound of any one of claims 41 - 50 , wherein R 6 is C 1-6 alkyl substituted with —SC(NH)NH 2 .
58 . The compound of any one of claims 41 - 50 , wherein R 6 is C 1-6 alkyl optionally substituted with halogen.
59 . The compound of any one of claims 41 - 50 and 58 , wherein R 6 is C 1-6 alkyl optionally substituted with fluoro.
60 . The compound of any one of claims 41 - 59 , wherein X is selected from a 5-membered heterocyclyl ring and phenyl, wherein each of the 5-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X .
61 . The compound of any one of claims 41 - 60 , wherein X is a 5-membered heterocyclyl ring optionally substituted with one or more R X .
62 . The compound of any one of claims 41 - 61 , wherein X is a pyrrolidinyl optionally substituted with one or more R X .
63 . The compound of any one of claims 41 - 62 , wherein X is a 2- or 3-pyrrolidinyl optionally substituted with one or more R X .
64 . The compound of any one of claims 41 - 60 , wherein X is phenyl optionally substituted with one or more R X .
65 . The compound of any one of claims 41 - 60 and 64 , wherein X is phenyl optionally substituted with three R X .
66 . The compound of any one of claims 41 - 65 , wherein R X is independently selected from halogen, C 1-6 alkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b .
67 . The compound of any one of claims 41 - 66 , wherein R X is independently selected from halogen and C 1-6 alkyl optionally substituted with one or more R b .
68 . The compound of any one of claims 41 - 66 , wherein R b is selected from C 2-6 alkenyl, OR c , N(R c ) 2 , and C 3-6 cycloalkyl.
69 . The compound of any one of claims 41 - 66 and 68 , wherein R b is selected from C 2-6 alkenyl, OR c , NH 2 , and cyclopropyl.
70 . The compound of claim 69 , wherein R c is selected from H and C 1-6 alkyl.
71 . The compound of claim 69 , wherein R b is selected from vinyl, OH, and NH 2 .
72 . The compound of any one of claims 41 - 71 , wherein two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring.
73 . A compound of Formula (IB):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
X is selected from a 5- or 6-membered heterocyclyl ring and phenyl, wherein each of the 5- or 6-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X ;
each R X is independently selected from halogen, C 1-6 alkyl, C 1-4 haloalkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b ;
or two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring;
each R b is independently selected from C 2-6 alkenyl, OR c , N(R c ) 2 , —C(O)OR c , C 3-6 cycloalkyl, and aryl;
each R c is independently selected from H, C 1-6 alkyl, aryl, —C(O)aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 .
74 . The compound of claim 73 , wherein X is selected from a 5-membered heterocyclyl ring and phenyl, wherein each of the 5-membered heterocyclyl ring and phenyl is optionally substituted with one or more R X .
75 . The compound of any one of claims 73 and 74 , wherein X is a 5-membered heterocyclyl ring optionally substituted with one or more R X .
76 . The compound of any one of claims 73 - 75 , wherein X is a pyrrolidinyl optionally substituted with one or more R X .
77 . The compound of any one of claims 73 - 76 , wherein X is a 2- or 3-pyrrolidinyl optionally substituted with one or more R X .
78 . The compound of any one of claims 73 and 74 , wherein X is phenyl optionally substituted with one or more R X .
79 . The compound of any one of claims 73 , 74 , and 78 , wherein X is phenyl optionally substituted with three R X .
80 . The compound of any one of claims 73 - 79 , wherein R X is independently selected from halogen, C 1-6 alkyl, OR c , N(R c ) 2 , —C(O)OR c , —C(O)R c , C 3-6 cycloalkyl, and aryl, wherein the C 1-6 alkyl is optionally substituted with one or more R b .
81 . The compound of any one of claims 73 - 79 , wherein R X is independently selected from halogen and C 1-6 alkyl optionally substituted with one or more R b .
82 . The compound of claim 81 , wherein R b is selected from C 2-6 alkenyl, OR c , N(R c ) 2 , and C 3-6 cycloalkyl.
83 . The compound of any one of claims 81 and 82 , wherein R b is selected from C 2-6 alkenyl, OR c , NH 2 , and cyclopropyl.
84 . The compound of any one of claims 73 - 83 , wherein R c is selected from H and C 1-6 alkyl.
85 . The compound of any one of claims 81 - 83 , wherein R b is selected from vinyl, OH, and NH 2 .
86 . The compound of any one of claims 73 - 85 , wherein two adjacent R X come together with the atoms to which they are attached to form a 5- or 6-membered ring.
87 . A compound of Formula (II):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R 1 is selected from H and C 1-3 alkyl;
R 2 is selected from H and C 1-3 alkyl;
R 3 is selected from H and C 1-3 alkyl;
or R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring;
R 4 is selected from H and C 1-3 alkyl;
R 5 is selected from H and C 1-6 alkyl;
R 6 is selected from H, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , —SC(NH)NH 2 , C 3-6 cycloalkyl, or C 3-6 heterocyclyl;
R 7 is selected from H and C 1-6 alkyl;
or R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring having one of the formulas:
wherein the ring is optionally substituted on a ring carbon atom with C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH;
or R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form a ring having one of the formulas:
R 8 is selected from H and halogen;
R 9 is selected from H and halogen;
R 10 is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl;
R 11 is selected from C 1-3 alkyl, C 2-4 alkenyl, and C 3-6 cycloalkyl, wherein the C 1-3 alkyl is optionally substituted with one or more R b ;
R 17 is selected from H, halogen, and C 1-6 alkyl;
each R a is independently selected from H and C 1-6 alkyl;
each R b is independently selected from OR c , —C(O)OR c , and —(O)aryl, wherein the aryl is optionally substituted with one or more R d ;
each R c is independently selected from hydrogen, C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , —C(O)aryl, and aryl; and
each R d is C 1-3 alkyl.
88 . The compound of claim 87 , wherein each of R 1 , R 2 , and R 3 is H.
89 . The compound of claim 87 , wherein two of R 1 , R 2 , and R 3 are H, and the other is C 1-3 alkyl.
90 . The compound of any one of claims 87 and 89 , wherein two of R 1 , R 2 , and R 3 are H, and the other is methyl.
91 . The compound of claim 87 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are C 1-3 alkyl.
92 . The compound of any one of claims 87 and 91 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are methyl.
93 . The compound of claim 87 , wherein R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring.
94 . The compound of any one of claim 87 or 93 , wherein R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form an imidazoline.
95 . The compound of any one of claims 87 - 94 , wherein R 4 is H.
96 . The compound of any one of claims 87 - 94 , wherein R 4 is C 1-3 alkyl.
97 . The compound of any one of claims 87 - 96 , wherein one of R 5 and R 7 is H and the other is C 1-6 alkyl.
98 . The compound of any one of claims 87 - 97 , wherein R 5 is H and R 7 is C 1-6 alkyl.
99 . The compound of any one of claims 87 - 96 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
100 . The compound of any one of claims 87 - 96 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
wherein the ring is optionally substituted with C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH.
101 . The compound of any one of claims 87 - 96 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
102 . The compound of any one of claims 87 - 96 , wherein R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
103 . The compound of any one of claims 87 - 96 , wherein R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring of formula
104 . The compound of any one of claims 87 - 96 , wherein R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring of formula
105 . The compound of any one of claims 87 - 102 , wherein R 6 is selected from H and C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR.
106 . The compound of any one of claims 87 - 102 and 105 , wherein R 6 is H.
107 . The compound of any one of claims 87 - 102 and 105 , wherein R 6 is C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR a .
108 . The compound of any one of claims 87 - 102 , 105 , and 107 , wherein R 6 is C 1-6 alkyl optionally substituted with OR.
109 . The compound of any one of claims 87 - 105 , 107 , and 108 , wherein R a is H.
110 . The compound of any one of claims 87 - 105 , 107 , and 108 , wherein R a is C 1-6 alkyl.
111 . The compound of any one of claims 87 - 102 , wherein R 6 is C 1-6 alkyl substituted with —SC(NH)NH 2 .
112 . The compound of any one of claims 87 - 102 , 105 , and 107 , wherein R 6 is C 1-6 alkyl optionally substituted with halogen.
113 . The compound of any one of claims 87 - 102 , 105 , 107 , and 112 , wherein R 6 is C 1-6 alkyl optionally substituted with fluoro.
114 . The compound of any one of claims 87 - 113 , wherein R 8 is H.
115 . The compound of any one of claims 87 - 114 , wherein one of R 9 and R 10 is halogen and the other is H.
116 . The compound of any one of claims 87 - 114 , wherein each of R 9 and R 10 is halogen.
117 . The compound of any one of claims 87 - 114 and 116 , wherein R 9 is fluoro and R 10 is chloro.
118 . The compound of any one of claims 87 - 114 , wherein R 9 is H and R 10 is C 1-4 alkyl.
119 . The compound of any one of claims 87 - 114 , wherein R 9 is halogen and R 10 is C 1-4 alkyl.
120 . The compound of any one of claims 87 - 114 and 119 , wherein R 9 is chloro and R 10 is C 1-4 alkyl.
121 . The compound of any one of claims 87 - 114 and 119 , wherein R 9 is fluoro and R 10 is C 1-4 alkyl.
122 . The compound of any one of claims 87 - 114 and 118 - 121 , wherein R 10 is ethyl.
123 . The compound of any one of claims 87 - 114 and 118 - 121 , wherein R 10 is isopropyl.
124 . The compound of any one of claims 87 - 114 , wherein R 9 is H and R 10 is C 3-6 cycloalkyl.
125 . The compound of any one of claims 87 - 114 and 124 , wherein R 10 is cyclopropyl.
126 . The compound of any one of claims 87 - 114 and 124 , wherein R 10 is cyclopentyl.
127 . The compound of any one of claims 87 - 126 , wherein R 11 is selected from C 1-3 alkyl optionally substituted with one or more R, and C 2-4 alkenyl.
128 . The compound of any one of claims 87 - 126 , wherein R 11 is selected from C 1-3 alkyl optionally substituted with one or more R, and C 3-6 cycloalkyl.
129 . The compound of any one of claims 87 - 128 , wherein R 11 is C 1-3 alkyl optionally substituted with one or more R b .
130 . The compound of any one of claims 127 - 129 , wherein R b is OR c , and wherein R c is selected from H and C 1-3 alkyl.
131 . The compound of claim 130 , wherein R c is H.
132 . The compound of claim 130 , wherein R c is C 1-3 alkyl.
133 . The compound of any one of claims 87 - 129 , wherein R 11 is C 1-3 alkyl.
134 . The compound of any one of claims 87 - 129 and 133 , wherein R 11 is methyl.
135 . The compound of any one of claims 87 - 126 and 128 , wherein R 11 is C 3-6 cycloalkyl.
136 . The compound of any one of claims 87 - 126 , 128 , and 135 , wherein R 11 is cyclopropyl.
137 . The compound of any one of claims 87 - 136 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (R).
138 . The compound of any one of claims 87 - 137 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
139 . The compound of any one of claims 87 - 138 , wherein R 17 is H.
140 . The compound of any one of claims 87 - 138 , wherein R 17 is halogen.
141 . The compound of any one of claims 87 - 114 , 116 , 129 , and 137 - 140 , wherein each of R 9 and R 10 is halogen, and R 11 is C 1-3 alkyl optionally substituted with one or more R b .
142 . The compound of claim 141 , wherein R 9 is fluoro, R 10 is chloro, and R 11 is C 1-3 alkyl optionally substituted with one or more R b .
143 . The compound of claim 142 , wherein R 9 is fluoro, R 10 is chloro, and R 11 is methyl.
144 . The compound of claim 143 , wherein R 9 is fluoro, R 10 is chloro, R 11 is methyl, and wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
145 . The compound of any one of claims 87 , 97 - 102 , 114 , 139 , and 140 , wherein each of R 1 , R 2 , and R 3 is H; R 4 is H; R 6 is C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR a ; R 9 is fluoro, R 10 is chloro, and R 11 is methyl.
146 . The compound of any one of claims 87 , 97 - 102 , 114 , 139 , and 140 , wherein each of R 1 , R 2 , and R 3 is H; R 4 is H; R 6 is H or C 1-6 alkyl; R 9 is fluoro, R 10 is chloro, R 11 is methyl, and wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
147 . The compound of any one of claims 87 , 114 , 139 , and 140 , wherein each of R 1 , R 2 , and R 3 is H; R 4 is H; R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring of formula
R 9 is fluoro; R 10 is chloro; and R 11 is methyl.
148 . The compound of any one of claims 87 , 114 , 139 , and 140 , wherein each of R 1 , R 2 , and R 3 is H; R 4 is H; R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form
R 6 ; R 6 is H or C 1-6 alkyl; R 9 is fluoro, R 10 is chloro, R 11 is methyl, and wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
149 . A compound of Formula (IIA):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R 1 is selected from H and C 1-3 alkyl;
R 2 is selected from H and C 1-3 alkyl;
R 3 is selected from H and C 1-3 alkyl;
R 4 is selected from H and C 1-3 alkyl;
R 6 is selected from H, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen and OR a ;
R 9 is selected from H and halogen;
R 10 is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl
R 11 is selected from C 1-3 alkyl, C 2-4 alkenyl, and C 3-6 cycloalkyl, wherein the C 1-3 alkyl is optionally substituted with one or more R b ;
each R a is independently selected from H and C 1-6 alkyl;
each R b is independently selected from OR c , —C(O)OR c , and —(O)aryl, wherein the aryl is optionally substituted with one or more R d ;
each R c is independently selected from hydrogen, C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , —C(O)aryl, and aryl; and
each R d is C 1-3 alkyl.
150 . The compound of claim 149 , wherein each of R 1 , R 2 , and R 3 is H.
151 . The compound of claim 149 , wherein two of R 1 , R 2 , and R 3 are H, and the other is C 1-3 alkyl.
152 . The compound of any one of claims 149 and 151 , wherein two of R 1 , R 2 , and R 3 are H, and the other is methyl.
153 . The compound of claim 149 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are C 1-3 alkyl.
154 . The compound of any one of claims 149 and 153 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are methyl.
155 . The compound of claim 149 , wherein R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring.
156 . The compound of any one of claims 149 and 155 , wherein R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form an imidazoline.
157 . The compound of any one of claims 149 - 156 , wherein R 4 is H.
158 . The compound of any one of claims 149 - 156 , wherein R 6 is selected from H and C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR.
159 . The compound of any one of claims 149 - 158 , wherein R 6 is H.
160 . The compound of any one of claims 149 - 158 , wherein R 6 is C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR a .
161 . The compound of any one of claims 149 - 158 and 160 , wherein R 6 is C 1-6 alkyl optionally substituted with OR a .
162 . The compound of any one of claims 149 - 158 and 160 - 161 , wherein R a is H.
163 . The compound of any one of claims 149 - 158 and 160 - 161 , wherein R a is C 1-6 alkyl.
164 . The compound of any one of claims 149 - 158 and 160 , wherein R 6 is C 1-6 alkyl optionally substituted with halogen.
165 . The compound of any one of claims 149 - 158 , 160 , and 164 , wherein R 6 is C 1-6 alkyl optionally substituted with fluoro.
166 . The compound of any one of claims 149 - 165 , wherein one of R 9 and R 10 is halogen and the other is H.
167 . The compound of any one of claims 149 - 165 , wherein each of R 9 and R 10 is halogen.
168 . The compound of any one of claims 149 - 165 and 167 , wherein R 9 is fluoro and R 10 is chloro.
169 . The compound of any one of claims 149 - 165 , wherein R 9 is H and R 10 is C 1-4 alkyl.
170 . The compound of any one of claims 149 - 165 , wherein R 9 is halogen and R 10 is C 1-4 alkyl.
171 . The compound of any one of claims 149 - 165 and 170 , wherein R 9 is chloro and R 10 is C 1-4 alkyl.
172 . The compound of any one of claims 149 - 165 and 170 , wherein R 9 is fluoro and R 10 is C 1-4 alkyl.
173 . The compound of any one of claims 149 - 165 and 169 - 172 , wherein R 10 is ethyl.
174 . The compound of any one of claims 149 - 165 and 169 - 172 , wherein R 10 is isopropyl.
175 . The compound of any one of claims 149 - 165 , wherein R 9 is H and R 10 is C 3-6 cycloalkyl.
176 . The compound of any one of claims 149 - 165 and 175 , wherein R 10 is cyclopropyl.
177 . The compound of any one of claims 149 - 165 and 175 , wherein R 10 is cyclopentyl.
178 . The compound of any one of claims 149 - 177 , wherein R 11 is selected from C 1-3 alkyl optionally substituted with one or more R b , and C 2-4 alkenyl.
179 . The compound of any one of claims 149 - 177 , wherein R 11 is selected from C 1-3 alkyl optionally substituted with one or more R b , and C 3-6 cycloalkyl.
180 . The compound of any one of claims 149 - 179 , wherein R 11 is C 1-3 alkyl optionally substituted with one or more R b .
181 . The compound of any one of claims 178 - 180 , wherein R b is OR c , and wherein R c is selected from H and C 1-3 alkyl.
182 . The compound of claim 181 , wherein R c is H.
183 . The compound of claim 181 , wherein R c is C 1-3 alkyl.
184 . The compound of any one of claims 149 - 179 , wherein R 11 is C 1-3 alkyl.
185 . The compound of any one of claims 149 - 179 and 184 , wherein R 11 is methyl.
186 . The compound of any one of claims 149 - 177 and 179 , wherein R 11 is C 3-6 cycloalkyl.
187 . The compound of any one of claims 149 - 177 , 179 , and 186 , wherein R 11 is cyclopropyl.
188 . The compound of any one of claims 149 - 187 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (R).
189 . The compound of any one of claims 149 - 188 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
190 . The compound of any one of claims 149 - 165 , wherein each of R 9 and R 10 is halogen, and R 11 is C 1-3 alkyl optionally substituted with one or more R b .
191 . The compound of any one of claims 149 - 165 and 190 , wherein R 9 is fluoro, R 10 is chloro, and R 11 is C 1-3 alkyl optionally substituted with one or more R b .
192 . The compound of any one of claims 149 - 165 , 190 , and 191 , wherein R 9 is fluoro, R 10 is chloro, and R 11 is methyl.
193 . The compound of any one of claims 149 - 165 and 190 - 192 , wherein R 9 is fluoro, R 10 is chloro, R 11 is methyl, and wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
194 . The compound of claim 149 , wherein each of R 1 , R 2 , and R 3 is H; R 4 is H; R 6 is C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen and OR a ; R 9 is fluoro, R 10 is chloro, and R 11 is methyl.
195 . The compound of any one of claims 149 and 194 , wherein each of R 1 , R 2 , and R 3 is H; R 4 is H; R 6 is H or C 1-6 alkyl; R 9 is fluoro, R 10 is chloro, R 11 is methyl, and wherein the Cahn-Ingold-Prelog configuration at the carbon atom R is bonded to is (S).
196 . A compound of Formula (IIB):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R 9 is selected from H and halogen;
R 10 is selected from H, halogen, C 1-4 alkyl, C 1-4 haloalkyl, and C 3-6 cycloalkyl;
R 11 is selected from C 1-3 alkyl, C 2-4 alkenyl, and C 3-6 cycloalkyl, wherein the C 1-3 alkyl is optionally substituted with one or more R b ;
each R b is independently selected from OR c , —C(O)OR c , and —(O)aryl, wherein the aryl is optionally substituted with one or more R d ;
each R c is independently selected from hydrogen, C 1-3 alkyl, OH, O(C 1-3 alkyl), NO 2 , —C(O)aryl, and aryl; and
each R d is C 1-3 alkyl.
197 . The compound of claim 196 , wherein one of R 9 and R 10 is halogen and the other is H.
198 . The compound of claim 196 , wherein each of R 9 and R 10 is halogen.
199 . The compound of any one of claims 196 and 198 , wherein R 9 is fluoro and R 10 is chloro.
200 . The compound of any one of claim 196 , wherein R 9 is H and R 10 is C 1-4 alkyl.
201 . The compound of any one of claim 196 , wherein R 9 is halogen and R 10 is C 1-4 alkyl.
202 . The compound of any one of claims 196 and 201 , wherein R 9 is chloro and R 10 is C 1-4 alkyl.
203 . The compound of any one of claims 196 and 201 , wherein R 9 is fluoro and R 10 is C 1-4 alkyl.
204 . The compound of any one of claims 196 and 200 - 203 , wherein R 10 is ethyl.
205 . The compound of any one of claims 196 and 200 - 203 , wherein R 10 is isopropyl.
206 . The compound of claim 196 , wherein R 9 is H and R 10 is C 3-6 cycloalkyl.
207 . The compound of any one of claims 196 and 206 , wherein R 10 is cyclopropyl.
208 . The compound of any one of claims 196 and 206 , wherein R 10 is cyclopentyl.
209 . The compound of any one of claims 196 - 208 , wherein R 11 is selected from C 1-3 alkyl optionally substituted with one or more R b , and C 2-4 alkenyl.
210 . The compound of any one of claims 196 - 208 , wherein R 11 is selected from C 1-3 alkyl optionally substituted with one or more R b , and C 3-6 cycloalkyl.
211 . The compound of any one of claims 196 - 210 , wherein R 11 is C 1-3 alkyl optionally substituted with one or more R b .
212 . The compound of any one of claims 196 and 209 - 211 , wherein R b is OR c , and wherein R c is selected from H and C 1-3 alkyl.
213 . The compound of claim 212 , wherein R c is H.
214 . The compound of claim 212 , wherein R c is C 1-3 alkyl.
215 . The compound of any one of claims 196 - 211 , wherein R 11 is C 1-3 alkyl.
216 . The compound of any one of claims 196 - 211 and 215 , wherein R 11 is methyl.
217 . The compound of any one of claims 196 - 208 and 210 , wherein R 11 is C 3-6 cycloalkyl.
218 . The compound of any one of claims 196 - 208 , 210 , and 217 , wherein R 11 is cyclopropyl.
219 . The compound of any one of claims 196 - 218 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (R).
220 . The compound of any one of claims 196 - 219 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
221 . The compound of claim 196 , wherein each of R 9 and R 10 is halogen, and R 11 is C 1-3 alkyl optionally substituted with one or more R b .
222 . The compound of any one of claims 196 and 221 , wherein R 9 is fluoro, R 10 is chloro, and R 11 is C 1-3 alkyl optionally substituted with one or more R b .
223 . The compound of any one of claims 196 , 221 , and 222 , wherein R 9 is fluoro, R 10 is chloro, and R 11 is methyl.
224 . The compound of any one of claims 196 and 221 - 223 , wherein R 9 is fluoro, R 10 is chloro, R 11 is methyl, and wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 11 is bonded to is (S).
225 . A compound of Formula (III):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R 1 is selected from H and C 1-3 alkyl;
R 2 is selected from H and C 1-3 alkyl;
R 3 is selected from H and C 1-3 alkyl;
or R 2 and R 3 together with the nitrogen atoms to which they are attached and the carbon atom connecting the two nitrogen atoms form a 5- or 6-membered ring;
R 4 is selected from H and C 1-3 alkyl;
R 5 is selected from H and C 1-6 alkyl;
R 6 is selected from H, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , and —SC(NH)NH 2 ;
R 7 is selected from H and C 1-6 alkyl;
or R 6 and R 7 together with the carbon and nitrogen atoms to which they are attached form a ring having one of the formulas:
wherein the ring is optionally substituted on a carbon atom with C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more OH;
or R 5 and R 7 together with the carbon atoms to which they are attached and the nitrogen atom connecting the two carbon atoms form a ring having one of the formulas:
R 8 is selected from H and halogen;
R 12 is selected from H, halogen, and C 1-6 alkyl;
R 13 is selected from H, halogen, C 1-6 alkyl, OR c , N(R c ) 2 , wherein C 1-6 alkyl is optionally substituted with one or more of OR c and aryl;
R 14 is selected from H and aryl;
or R 13 and R 14 together with the carbon atoms to which they are attached form a 5- or 6-membered cycloalkyl ring;
R 15 is selected from H, C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with one or more R b ;
each R a is independently selected from H and C 1-6 alkyl;
each R b is independently selected from C 2-6 alkenyl, OR c , N(R c ) 2 , —C(O)OR c , C 3-6 cycloalkyl, and aryl;
each R c is independently selected from hydrogen, C 1-6 alkyl, aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from OH, O(C 1-3 alkyl), NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 .
226 . The compound of claim 225 , wherein each of R 1 , R 2 , and R 3 is H.
227 . The compound of claim 225 , wherein two of R 1 , R 2 , and R 3 are H, and the other is C 1-3 alkyl.
228 . The compound of any one of claims 225 and 227 , wherein two of R 1 , R 2 , and R 3 are H, and the other is methyl.
229 . The compound of claim 225 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are C 1-3 alkyl.
230 . The compound of any one of claims 225 and 229 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are methyl.
231 . The compound of any one of claims 225 - 230 , wherein R 4 is H.
232 . The compound of any one of claims 225 - 231 , wherein R 6 is selected from H or C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , or —SC(NH)NH 2 .
233 . The compound of any one of claims 225 - 232 , wherein R 6 is H.
234 . The compound of any one of claims 225 - 233 , wherein R 8 is H.
235 . The compound of any one of claims 225 - 234 , wherein each of R 12 and R 13 is H.
236 . The compound of any one of claims 225 - 234 , wherein each of R 12 and R 13 is not H.
237 . The compound of any one of claims 225 - 234 , wherein one of R 12 and R 13 is H, and the other is not H.
238 . The compound of any one of claims 225 - 234 and 237 , wherein R 12 is H, and R 13 is C 1-6 alkyl optionally substituted with one or more of OR c or aryl.
239 . The compound of any one of claims 225 - 234 and 237 - 238 , wherein R 12 is H, and R 13 is C 1-6 alkyl optionally substituted with OR.
240 . The compound of any one of claims 225 - 234 and 237 - 239 , wherein R 12 is H, and R 13 is C 1-6 alkyl.
241 . The compound of any one of claims 225 - 234 and 237 - 240 , wherein R 12 is H, and R 13 is halogen.
242 . The compound of any one of claims 225 - 234 and 237 - 241 , wherein R 12 is H, and R 13 is fluoro.
243 . The compound of any one of claims 225 - 234 and 236 , wherein each of R 12 and R 13 is C 1-6 alkyl.
244 . The compound of any one of claims 225 - 234 and 236 , wherein each of R 12 and R 13 is halogen.
245 . The compound of any one of claims 225 - 234 , 236 , and 244 , wherein each of R 12 and R 13 is fluoro.
246 . The compound of any one of claims 225 - 234 and 237 , wherein R 12 is H, and R 13 is OR.
247 . The compound of any one of claims 225 - 234 and 237 , wherein R 12 is H, and R 13 is N(R c ) 2 .
248 . The compound of any one of claims 246 and 247 , wherein each R c is selected from H or C 1-6 alkyl.
249 . The compound of any one of claims 246 and 247 , wherein each R c is selected from C 1-6 alkyl or —(CH 2 )aryl.
250 . The compound of any one of claims 246 , 247 , and 248 , wherein each R c is H.
251 . The compound of any one of claims 246 and 247 - 249 , wherein each R c is C 1-6 alkyl.
252 . The compound of any one of claims 246 , 247 - 249 , and 251 , wherein each R c is methyl.
253 . The compound of any one of claims 246 , 247 , and 249 , wherein each R c is —(CH 2 )aryl.
254 . The compound of any one of claim 247 , wherein one R c is H and the other R c is C 1-6 alkyl.
255 . The compound of any one of claims 225 - 254 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 13 is bonded to is (R).
256 . The compound of any one of claims 225 - 254 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 13 is bonded to is (S).
257 . The compound of any one of claims 225 - 256 , wherein R 14 is H.
258 . The compound of any one of claims 225 - 256 , wherein R 14 is aryl.
259 . The compound of any one of claims 225 - 258 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 14 is bonded to is (R).
260 . The compound of any one of claims 225 - 258 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 14 is bonded to is (S).
261 . The compound of any one of claims 225 - 260 , wherein R 15 is H.
262 . The compound of any one of claims 225 - 261 , wherein R 15 is C 1-6 alkyl optionally substituted with one or more R b .
263 . The compound of any one of claims 225 - 261 , wherein R 15 is C 1-6 alkyl optionally substituted with one R b .
264 . The compound of any one of claims 225 - 263 , wherein R 15 is C 4-5 alkyl optionally substituted with one R b .
265 . The compound of any one of claims 262 - 264 , wherein R b is selected from OR c , N(R c ) 2 , and cyclopropyl.
266 . The compound of any one of claims 262 - 265 , wherein R b is N(R c ) 2 .
267 . The compound of any one of claims 262 - 266 , wherein R b is NH 2 .
268 . A compound of Formula (IIIA):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R 1 is selected from H and C 1-3 alkyl;
R 2 is selected from H and C 1-3 alkyl;
R 3 is selected from H and C 1-3 alkyl;
R 4 is selected from H and C 1-3 alkyl;
R 6 is selected from H, C 1-6 alkyl, and C 2-6 alkenyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , and —SC(NH)NH 2 ;
R 8 is selected from H and halogen;
R 12 is selected from H, halogen, and C 1-6 alkyl;
R 13 is selected from H, halogen, C 1-6 alkyl, OR c , N(R c ) 2 , wherein C 1-6 alkyl is optionally substituted with one or more of OR c and aryl;
R 14 is selected from H and aryl;
or R 13 and R 14 together with the carbon atoms to which they are attached form a 5- or 6-membered cycloalkyl ring;
R 16 is C 1-6 alkyl;
each R a is independently selected from H and C 1-6 alkyl;
each R c is independently selected from hydrogen, C 1-6 alkyl, aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from OH, O(C 1-3 alkyl), NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 .
269 . The compound of claim 268 , wherein each of R 1 , R 2 , and R 3 is H.
270 . The compound of claim 268 , wherein two of R 1 , R 2 , and R 3 are H, and the other is C 1-3 alkyl.
271 . The compound of any one of claims 268 and 270 , wherein two of R 1 , R 2 , and R 3 are H, and the other is methyl.
272 . The compound of claim 268 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are C 1-3 alkyl.
273 . The compound of any one of claims 268 and 272 , wherein one of R 1 , R 2 , and R 3 is H, and the other two are methyl.
274 . The compound of any one of claims 268 - 273 , wherein R 4 is H.
275 . The compound of any one of claims 268 - 274 , wherein R 6 is selected from H or C 1-6 alkyl optionally substituted with one or more substituents selected from the group consisting of halogen, OR a , SR a , —C(O)OR a , or —SC(NH)NH 2 .
276 . The compound of any one of claims 268 - 275 , wherein R 6 is H.
277 . The compound of any one of claims 268 - 276 , wherein R 8 is H.
278 . The compound of any one of claims 268 - 277 , wherein each of R 12 and R 13 is H.
279 . The compound of any one of claims 268 - 277 , wherein each of R 12 and R 13 is not H.
280 . The compound of any one of claims 268 - 277 , wherein one of R 12 and R 13 is H, and the other is not H.
281 . The compound of any one of claims 268 - 277 , wherein R 12 is H, and R 13 is C 1-6 alkyl optionally substituted with one or more of OR c or aryl.
282 . The compound of any one of claims 268 - 277 and 281 , wherein R 12 is H, and R 13 is C 1-6 alkyl optionally substituted with OR c .
283 . The compound of any one of claims 268 - 277 , 281 , and 282 , wherein R 12 is H, and R 13 is C 1-6 alkyl.
284 . The compound of any one of claims 268 - 277 and 280 , wherein R 12 is H, and R 13 is halogen.
285 . The compound of any one of claims 268 - 277 , 280 , and 284 , wherein R 12 is H, and R 13 is fluoro.
286 . The compound of any one of claims 268 - 277 and 279 , wherein each of R 12 and R 13 is C 1-6 alkyl.
287 . The compound of any one of claims 268 - 277 and 279 , wherein each of R 12 and R 13 is halogen.
288 . The compound of any one of claims 268 - 277 and 279 , wherein each of R 12 and R 13 is fluoro.
289 . The compound of any one of claims 268 - 277 and 280 , wherein R 12 is H, and R 13 is OR.
290 . The compound of any one of claims 268 - 277 and 280 , wherein R 12 is H, and R 13 is N(R c ) 2 .
291 . The compound of any one of claims 289 and 290 , wherein each R c is selected from H or C 1-6 alkyl.
292 . The compound of any one of claims 289 and 290 , wherein R c is selected from C 1-6 alkyl or —(CH 2 )aryl.
293 . The compound of any one of claims 289 and 290 , wherein R c is H.
294 . The compound of any one of claims 289 and 290 , wherein R c is C 1-6 alkyl.
295 . The compound of any one of claims 289 and 290 , wherein R c is methyl.
296 . The compound of any one of claims 289 and 290 , wherein R c is —(CH 2 )aryl.
297 . The compound of claim 290 , wherein one R c is H and the other R c is C 1-6 alkyl.
298 . The compound of any one of claims 268 - 297 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 13 is bonded to is (R).
299 . The compound of any one of claims 268 - 297 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 13 is bonded to is (S).
300 . The compound of any one of claims 268 - 299 , wherein R 14 is H.
301 . The compound of any one of claims 268 - 299 , wherein R 14 is aryl.
302 . The compound of any one of claims 268 - 301 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 14 is bonded to is (R).
303 . The compound of any one of claims 268 - 301 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 14 is bonded to is (S).
304 . The compound of any one of claims 268 - 303 , wherein R 16 is C 1-6 alkyl.
305 . The compound of any one of claims 268 - 304 , wherein R 16 is methyl.
306 . The compound of any one of claims 268 - 305 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 16 is bonded to is (S).
307 . The compound of any one of claims 268 - 305 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 16 is bonded to is (R).
308 . A compound of Formula (IIIB):
or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, wherein:
R 12 is selected from H, halogen, and C 1-6 alkyl;
R 13 is selected from H, halogen, C 1-6 alkyl, OR c , N(R c ) 2 , wherein C 1-6 alkyl is optionally substituted with one or more of OR c and aryl;
R 16 is C 1-6 alkyl;
each R c is independently selected from hydrogen, C 1-6 alkyl, aryl, and —(CH 2 )aryl, wherein the C 1-6 alkyl and the aryl are each optionally substituted with one or more R d ; and
each R d is independently selected from OH, O(C 1-3 alkyl), NH 2 , NH(C 1-3 alkyl), and N(C 1-3 alkyl) 2 .
309 . The compound of claim 308 , wherein each of R 12 and R 13 is H.
310 . The compound of claim 308 , wherein each of R 12 and R 13 is not H.
311 . The compound of claim 308 , wherein one of R 12 and R 13 is H, and the other is not H.
312 . The compound of any one of claims 308 and 311 , wherein R 12 is H, and R 13 is C 1-6 alkyl optionally substituted with one or more of OR c or aryl.
313 . The compound of any one of claims 308 and 311 - 312 , wherein R 12 is H, and R 13 is C 1-6 alkyl optionally substituted with OR c .
314 . The compound of any one of claims 308 and 311 - 313 , wherein R 12 is H, and R 13 is C 1-6 alkyl.
315 . The compound of any one of claims 308 and 311 , wherein R 12 is H, and R 13 is halogen.
316 . The compound of any one of claims 308 , 311 , 315 , wherein R 12 is H, and R 13 is fluoro.
317 . The compound of any one of claims 308 and 310 , wherein each of R 12 and R 13 is C 1-6 alkyl.
318 . The compound of any one of claims 308 and 310 , wherein each of R 12 and R 13 is halogen.
319 . The compound of any one of claims 308 , 310 , and 318 , wherein each of R 12 and R 13 is fluoro.
320 . The compound of any one of claims 308 and 311 , wherein R 12 is H, and R 13 is OR c .
321 . The compound of any one of claims 308 and 311 , wherein R 12 is H, and R 13 is N(R c ) 2 .
322 . The compound of any one of claims 320 and 321 , wherein each R c is selected from H or C 1-6 alkyl.
323 . The compound of any one of claims 320 and 321 , wherein each R c is selected from C 1-6 alkyl or —(CH 2 )aryl.
324 . The compound of any one of claims 320 and 321 , wherein each R c is H.
325 . The compound of any one of claims 320 and 321 , wherein each R c is C 1-6 alkyl.
326 . The compound of any one of claims 320 and 321 , wherein each R c is methyl.
327 . The compound of any one of claims 320 and 321 , wherein each R c is —(CH 2 )aryl.
328 . The compound of claim 321 , wherein one R c is H and the other R c is C 1-6 alkyl.
329 . The compound of any one of claims 308 - 328 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 13 is bonded to is (R).
330 . The compound of any one of claims 308 - 328 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 13 is bonded to is (S).
331 . The compound of any one of claims 308 - 330 , wherein R 16 is C 1-6 alkyl.
332 . The compound of any one of claims 308 - 331 , wherein R 16 is methyl.
333 . The compound of any one of claims 308 - 332 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 16 is bonded to is (S).
334 . The compound of any one of claims 308 - 332 , wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 16 is bonded to is (R).
335 . The compound of claim 308 , wherein one of R 12 and R 13 is H, and the other of R 12 and R 13 is not H; and R 16 is methyl, wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 16 is bonded to is (S).
336 . The compound of any one of claims 308 and 335 , wherein R 12 is H, and R 13 is OR c ; R c is selected from H or C 1-6 alkyl; and R 16 is methyl, wherein the Cahn-Ingold-Prelog configuration at the carbon atom R 16 is bonded to is (S).
337 . A compound selected from any one of the compounds listed in Table 1, or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer.
338 . A pharmaceutical composition comprising a compound of any one of claims 1 - 337 , or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, and a pharmaceutically acceptable carrier.
339 . A method of treating a microbial infection comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 - 337 , or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutically acceptable composition of claim 338 .
340 . A method of preventing a microbial infection comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 - 337 , or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutically acceptable composition of claim 338 .
341 . A method of reducing the risk of a microbial infection comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 - 337 , or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutically acceptable composition of claim 338 .
342 . A method of delaying the onset of a microbial infection comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1 - 337 , or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, or a pharmaceutically acceptable composition of claim 338 .
343 . Use of a compound according to any one of claims 1 - 337 , or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, in the manufacture of a medicament for treating, preventing, or reducing a microbial infection in a subject.
344 . A compound according to any one of claims 1 - 337 , or a tautomer thereof or a pharmaceutically acceptable salt of the compound or tautomer, for use in treating, preventing, or reducing a microbial infection in a subject.Cited by (0)
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