MMPL3 inhibitors, compositions and uses thereof

Patent metadata

Field	Value
Publication number	US-11655238-B2
Application number	US-201917295227-A
Country	US
Kind code	B2
Filing date	Nov 20, 2019
Priority date	Nov 20, 2018
Publication date	May 23, 2023
Grant date	May 23, 2023

Abstract

The present disclosure relates generally to inhibitors of mycobacterial membrane protein MmpL3, compositions comprising the inhibitors, and methods of preparation and use thereof.

First claim

What is claimed is:

1. A compound of the below Formula III:

or a pharmaceutically acceptable salt, tautomer, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof,
wherein:
X 1 , X 2 , and X 3 are C; X 4 and X 5 are N;
L 1 is *—N(R 1b )CO—, *—(CH 2 ) k —N(R 1b )CO—, *—(CH 2 ) n —N(R 1c )—(CH 2 ) k —N(R 1b )CO—, *—(CH 2 )n-(O(CH 2 ) m ) p —O(CH 2 ) k —N(R 1b )CO—, *—(CH 2 ) m —CO-L 1a -CO—, *—(CH 2 ) m -L 1a -CO—, *—(CH 2 ) n —NHCONH—(CH 2 ) m —, *—(CH 2 ) n —N(R 1c )—(CH 2 ) k —N(R 1b )—(CH 2 ) m —, *—(CH 2 ) n —CON(R 1b )—(CH 2 ) m —, *—(CH 2 ) p —N(R 1c )—(CH 2 ) n —CON(R 1b )—(CH 2 ) m —, *—(CH 2 ) p —N(R 1c )—(CH 2 ) n —SO 2 N(R 1b )—(CH 2 ) m —, *—(CH 2 ) n —SO 2 N(R 1b )—(CH 2 ) m —, *—(CH 2 ) n —OCO—, *—(CH 2 ) n -L 1a -(CH 2 ) m —, *—N(R 1c )—(CH 2 ) m —N(R 1b )—(CH 2 ) m —, or —N(R 1c )—(CH 2 ) n —N(R 1b )—N(R 1b )—(CO)—; wherein
* represents the point of connection with R 1 ;
L 1a is 5-, 6- or 7-membered heterocyclylene;
each R 1b is independently H or C 1-3 alkyl;
each R 1c is independently H or C 1-3 alkyl;
k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and
each m, n and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
R 1 is adamantly substituted with one to ten R 1a , bicyclo[2.2.1]heptyl substituted with one to ten R 1a or unsubstituted adamantyl;
each R 1a is independently selected from —CN, —NO 2 , C 1-3 alkyl, C 1-3 haloalkyl, —OR 6 , —SR 6 , —N(R 6 ) 2 , —C(O)R 6 , —C(O)OR 6 , —S(O)R 6 , —S(O) 2 R 6 , —C(O)N(R 6 ) 2 , —NR 6 C(O)R 6 , —NR 6 C(O)OR 6 , —NR 6 C(O)N(R 6 ) 2 , —NHS(O)R 6 , —S(O)(NH)R 6 , cycloalkyl, aryl, heterocyclyl, heteroaryl, or a combination thereof;
R 2 is C 1-3 alkyl;
each R 3b and R 3c is independently H or R 3a ; and
each R 4b and R 4c is independently H or R 4a ;
R 3a and R 4a is independently selected form halo and C 1-3 alkyl;
R 5 is absent;
each R 6 is independently hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, aryl, heteroaryl, or heterocyclyl.

2. The compound of claim 1 , which is of Formula I-C, II-C, III-C, IV-C, V-C, VII-C, VIII-C or IX-C:

or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, wherein
L 3 is *—(CH 2 ) n —, *—(CH 2 ) n —N(R 1b )—(CH 2 ) k — or *—(CH 2 ) n —(O(CH 2 ) m ) p —O(CH 2 ) k —,
L 4 is CO or SO 2 ,
s and t are independently 0, 1 or 2,
each m, n and p is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
k is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
and X 1 , X 2 , X 3 , X 4 , X 5 , R 1b , R 1c , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in claim 1 .

3. The compound of claim 1 , wherein
L 1 is selected from *—NHCONH—, *—NHCONHCH 2 —, *—CH 2 NHCONHCH 2 —, *—(CH 2 ) 2 NHCONHCH 2 —, *—(CH 2 ) 3 NHCONHCH 2 —, *—(CH 2 ) 4 NHCONHCH 2 —, *—(CH 2 ) 5 NHCONHCH 2 —, *—(CH 2 ) 6 NHCONHCH 2 —, *—NHCH 2 NHCO—, *—NH(CH 2 ) 2 NHCO—, *—NH(CH 2 ) 3 NHCO—, *—NH(CH 2 ) 4 NHCO—, *—NH(CH 2 ) 5 NHCO—, *—NH(CH 2 ) 6 NHCO—, *—NH(CH 2 ) 7 NHCO—, *—CH 2 NHCH 2 NHCO—, *—CH 2 NH(CH 2 ) 2 NHCO—, *—CH 2 NH(CH 2 ) 3 NHCO—, *—CH 2 NH(CH 2 ) 4 NHCO—, *—CH 2 NH(CH 2 ) 5 NHCO—, *—CH 2 NH(CH 2 ) 6 NHCO—, *—CH 2 NH(CH 2 ) 7 NHCO—, *—CH 2 NHCO—, *—(CH 2 ) 2 NHCO—, *—(CH 2 ) 3 NHCO—, *—(CH 2 ) 4 NHCO—, *—(CH 2 ) 5 NHCO—, *—(CH 2 ) 6 NHCO—, *—(CH 2 ) 7 NHCO—, *—(CH 2 ) 8 NHCO—, *—NHCO—, *—O(CH 2 ) 2 NHCO—, *—CH 2 NHCO—, *—CH 2 O(CH 2 ) 2 NHCO—, *—(CH 2 ) 2 O(CH 2 ) 2 NHCO—, *—(CH 2 ) 3 O(CH 2 ) 2 NHCO—, *—O(CH 2 ) 3 O(CH 2 ) 2 NHCO—, *—CH 2 O(CH 2 ) 2 O(CH 2 ) 2 NHCO—, *—(CH 2 ) 2 O(CH 2 ) 2 O(CH 2 ) 2 NHCO—, *—(CH 2 ) 3 O(CH 2 ) 2 O(CH 2 ) 2 NHCO—, *—O(CH 2 ) 3 NHCO—, *—NH(CH 2 ) 2 NHCH 2 —, *—NH(CH 2 ) 4 NHCH 2 —, *—NH(CH 2 ) 2 SO 2 NHCH 2 —, *—OC(O)—, *—CH 2 O(CH 2 ) 3 NHCO—, *—CH 2 NH(CH 2 ) 2 NHCH 2 —, *—CH 2 NH(CH 2 ) 4 NHCH 2 —, *—CH 2 NH(CH 2 ) 2 SO 2 NHCH 2 —, *—CH 2 OC(O)—,

4. The compound of claim 1 , wherein R 1 is selected from:

5. A compound, or a pharmaceutically acceptable salt, solvate, tautomer, isotopically enriched analog, stereoisomer, or mixture of stereoisomers thereof, wherein the compound is selected from any one of the following compounds:

Comp

No.
Structure
Name

1

1-((1r,3r,5r,7r)-adamantan-2- yl)-3-(5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl- 1H-pyrazol-3-yl)urea

2

1-((1r,3r,5r,7r)-adamantan-2- yl)-3-((5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl- 1H-pyrazol-3-yl)methyl)urea

3

1-(((1r,3r,5r,7r)-adamantan-2- yl)methyl)-3-((5-(4-chloro- phenyl)-1-(2,4-dichlorophenyl)- 4-methyl-1H-pyrazol-3-yl)- methyl)urea

4

1-(2-((1r,3r,5r,7r)-adamantan- 2-yl)ethyl)-3-((5-(4-chloro- phenyl)-1-(2,4-dichlorophenyl)- 4-methyl-1H-pyrazol-3-yl)- methyl)urea

5

1-(3-((1r,3r,5r,7r)-adamantan- 2-yl)propyl)-3-((5-(4-chloro- phenyl)-1-(2,4-dichlorophenyl)- 4-methyl-1H-pyrazol-3-yl)- methyl)urea

6

Assignees

• Univ Shanghai Technology

Inventors

• Rao Zihe
• Li Jun
• Zhang Bing
• Yang Haitao

Classifications

• C07D233/90

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D333/38

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D207/34

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title